US20080033333A1 - Solid dressing for treating wounded tissue - Google Patents

Solid dressing for treating wounded tissue Download PDF

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Publication number
US20080033333A1
US20080033333A1 US11/882,879 US88287907A US2008033333A1 US 20080033333 A1 US20080033333 A1 US 20080033333A1 US 88287907 A US88287907 A US 88287907A US 2008033333 A1 US2008033333 A1 US 2008033333A1
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US
United States
Prior art keywords
fibrinogen
thrombin
solid dressing
dressing
solid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/882,879
Inventor
Martin MacPhee
Dawson Beall
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
STB LIFESAVING TECHNOLOGIES Inc
Original Assignee
STB LIFESAVING TECHNOLOGIES Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by STB LIFESAVING TECHNOLOGIES Inc filed Critical STB LIFESAVING TECHNOLOGIES Inc
Priority to US11/882,879 priority Critical patent/US20080033333A1/en
Assigned to STB LIFESAVING TECHNOLOGIES, INC. reassignment STB LIFESAVING TECHNOLOGIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEALL, DAWSON, MACPHEE, MARTIN
Publication of US20080033333A1 publication Critical patent/US20080033333A1/en
Priority to US13/364,837 priority patent/US20120150087A1/en
Assigned to STB, LTD reassignment STB, LTD CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF ASSIGNEE PREVIOUSLY RECORDED ON REEL 020027 FRAME 0226. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR'S INTEREST. Assignors: BEALL, DAWSON, MACPHEE, MARTIN
Priority to US14/583,002 priority patent/US20150118284A1/en
Priority to US15/088,438 priority patent/US20160213806A1/en
Priority to US15/605,660 priority patent/US20180117210A1/en
Priority to US16/289,535 priority patent/US20200000957A1/en
Abandoned legal-status Critical Current

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    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/254Enzymes, proenzymes
    • AHUMAN NECESSITIES
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    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602Type of release, e.g. controlled, sustained, slow
    • A61L2300/604Biodegradation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings
    • A61L2300/608Coatings having two or more layers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/04Materials for stopping bleeding

Definitions

  • the present invention relates to a solid dressing for treating wounded tissue in a mammalian patient, such as a human.
  • haemostatic agents that have been developed to overcome the deficiencies of traditional gauze bandages. These haemostatic agents include the following:
  • TraumaDEXTM a starch-based haemostatic agent sold under the trade name TraumaDEXTM.
  • TraumaDEXTM This product comprises microporous polysaccharide particles that are poured directly into or onto a wound. The particles appear to exert their haemostatic effect by absorbing water from the blood and plasma in the wound, resulting in the accumulation and concentration of clotting factors and platelets.
  • this agent showed no meaningful benefit over standard gauze dressings. See McManus et al., Business Briefing: Emergency Medical Review 2005, pp. 76-79 (presently available on-line at www.touchbriefings.com/pdf/1334/Wedmore.pdf).
  • QuickClotTM powder a zeolite granular haemostatic agent that is poured directly into or onto a wound.
  • the zeolite particles also appear to exert their haemostatic effect through fluid absorption, which cause the accumulation and concentration of clotting factors and platelets.
  • this agent has been used successfully in some animal studies, there remains concern about the exothermic process of fluid absorption by the particles. Some studies have shown this reaction to produce temperatures in excess of 143° C. in vitro and in excess of 50° C. in vivo, which is severe enough to cause third-degree burns. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 77.
  • the exothermic reaction of QuikClotTM has also been observed to result in gross and histological tissue changes of unknown clinical significance. Acheson et al., J. Trauma 59:865-874 (2005).
  • the Rapid Deployment HemostatTM appears to exert its haemostatic effect through red blood cell aggregation, platelet activation, clotting cascade activation and local vasoconstriction.
  • the Rapid Deployment HemostatTM is an algae-derived dressing composed of poly-N-acetyl-glucosamine. While the original dressing design was effective in reducing minor bleeding, it was necessary to add gauze backing in order to reduce blood loss in swine models of aortic and liver injury. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 78.
  • HemConTM Chitosan Bandage is a freeze-dried chitosan dressing purportedly designed to optimize the mucoadhesive surface density and structural integrity of the chitosan at the site of the wound.
  • the HemConTM Chitosan Bandage apparently exerts its haemostatic effects primarily through adhesion to the wound, although there is evidence suggesting it may also enhance platelet function and incorporate red blood cells into the clot it forms on the wound.
  • This bandage has shown improved hemostasis and reduced blood loss in several animal models of arterial hemorrhage, but a marked variability was observed between bandages, including the failure of some due to inadequate adherence to the wound. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 79.
  • Liquid fibrin sealants such as Tisseel VH have been used for years as an operating room adjunct for hemorrhage control. See J. L. Garza et al., J. Trauma 30:512-513 (1990); H. B. Kram et al., J. Trauma 30:97-101(1990); M. G. Ochsner et al., J. Trauma 30:884-887 (1990); T. L. Matthew et al., Ann. Thorac. Surg. 50:40-44 (1990); H. Jakob et al., J. Vasc. Surg., 1:171-180 (1984). The first mention of tissue glue used for hemostasis dates back to 1909.
  • Liquid fibrin sealants are typically composed of fibrinogen and thrombin, but may also contain Factor XIII/XIIIa, either as a by-product of fibrinogen purification or as an added ingredient (in certain applications, it is therefore not necessary that Factor XIII/Factor XIIIa be present in the fibrin sealant because there is sufficient Factor XIII/XIIIa, or other transaminase, endogenously present to induce fibrin formation). As liquids, however, these fibrin sealants have not proved useful for treating traumatic injuries in the field.
  • Dry fibrinogen-thrombin dressings having a collagen support are also available for operating room use in many European countries. See U. Schiele et al., Clin. Materials 9:169-177 (1992). While these fibrinogen-thrombin dressings do not require the pre-mixing needed by liquid fibrin sealants, their utility for field applications is limited by a requirement for storage at 4° C. and the necessity for pre-wetting with saline solution prior to application to the wound. These dressings are also not effective against high pressure, high volume bleeding. See Sondeen et al., J. Trauma 54:280-285 (2003).
  • a dry fibrinogen/thrombin dressing for treating wounded tissue is also available from the American Red Cross (ARC).
  • ARC American Red Cross
  • this particular dressing is composed of a backing material and a plurality of layers, the outer two of which contain fibrinogen (but no thrombin) while the inner layer contains thrombin and calcium chloride (but no fibrinogen). While this dressing has shown great success in several animal models of hemorrhage, the bandage is fragile, inflexible, and has a tendency to break apart when handled. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 78; Kheirabadi et al., J. Trauma 59:25-35 (2005).
  • U.S. Pat. No. 4,683,142 discloses a resorptive sheet material for closing and healing wounds which consists of a glycoprotein matrix, such as collagen, containing coagulation proteins, such as fibrinogen and thrombin.
  • U.S. Pat. No. 5,702,715 discloses a reinforced biological sealant composed of separate layers of fibrinogen and thrombin, at least one of which also contains a reinforcement filler such as PEG, PVP, BSA, mannitol, FICOLL, dextran, myo-inositol or sodium chlorate.
  • a reinforcement filler such as PEG, PVP, BSA, mannitol, FICOLL, dextran, myo-inositol or sodium chlorate.
  • 6,056,970 discloses dressings composed of a bioabsorbable polymer, such as hyaluronic acid or carboxymethylcellulose, and a haemostatic composition composed of powdered thrombin and/or powdered fibrinogen.
  • U.S. Pat. No. 7,189,410 discloses a bandage composed of a backing material having thereon: (i) particles of fibrinogen; (ii) particles of thrombin; and (iii) calcium chloride.
  • U.S. Patent Application Publication No. US 2006/0155234 A1 discloses a dressing composed of a backing material and a plurality of fibrinogen layers which have discrete areas of thrombin between them. To date, none of these dressings have been approved for use or are available commercially.
  • a first embodiment of the present invention is direct to a solid dressing for treating wounded tissue in a mammal comprising at least one haemostatic layer consisting essentially of a fibrinogen component and thrombin, wherein the thrombin is present in an amount between about 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component.
  • Another embodiment is directed to a method of treating wounded tissue using a solid dressing comprising at least one haemostatic layer consisting essentially of a fibrinogen component and thrombin, wherein the thrombin is present in an amount between about 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component.
  • thrombin is between 0.125 Units/mg of fibrinogen component and 0.080 Units/mg of fibrinogen component, and the use of the same for treating wounded tissue.
  • FIG. 1A and FIG. 1B are graphs depicting the results of the EVPA and Adherence Assays.
  • FIG. 2 is a diagram of the set-up for the EVPA Assay.
  • Patient refers to human or animal individuals in need of medical care and/or treatment.
  • “Wound” as used herein refers to any damage to any tissue of a patient which results in the loss of blood from the circulatory system and/or any other fluid from the patient's body.
  • the tissue may be an internal tissue, such as an organ or blood vessel, or an external tissue, such as the skin.
  • the loss of blood may be internal, such as from a ruptured organ, or external, such as from a laceration.
  • a wound may be in a soft tissue, such as an organ, or in hard tissue, such as bone.
  • the damage may have been caused by any agent or source, including traumatic injury, infection or surgical intervention.
  • Resorbable material refers to a material that is broken down spontaneously in and/or by the mammalian body into components which are consumed or eliminated in such a manner as not to interfere significantly with wound healing and/or tissue regeneration, and without causing any significant metabolic disturbance.
  • “Stability” as used herein refers to the retention of those characteristics of a material that determine activity and/or function.
  • Suitable as used herein is intended to mean that a material does not adversely affect the stability of the dressings or any component thereof.
  • Binding agent refers to a compound or mixture of compounds that improves the adherence and/or cohesion of the components of the haemostatic layer(s) of the dressings.
  • Solubilizing agent refers to a compound or mixture of compounds that improves the dissolution of a protein or proteins in aqueous solvent.
  • Fill refers to a compound or mixture of compounds that provide bulk and/or porosity to the haemostatic layer(s) of a dressing.
  • Release agent refers to a compound or mixture of compounds that facilitates removal of a dressing from a manufacturing mold.
  • “Foaming agent” as used herein refers to a compound or mixture of compounds that produces gas when hydrated under suitable conditions.
  • Solid as used herein is intended to mean that the dressing will not substantially change in shape or form when placed on a rigid surface, wound-facing side down, and then left to stand at room temperature for 24 hours.
  • a first preferred embodiment of the present invention is directed to a solid dressing for treating wounded tissue in a patient which comprises a haemostatic layer consisting essentially of a fibrinogen component and thrombin, wherein the thrombin is present in an amount between 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component.
  • the fibrinogen component and the thrombin are the only necessary and essential ingredients of the haemostatic layer(s) of the solid dressing when it is used as intended to treat wounded tissue.
  • the haemostatic layer may contain other ingredients in addition to the fibrinogen component and the thrombin as desired for a particular application, but these other ingredients are not required for the solid dressing to function as intended under normal conditions, i.e. these other ingredients are not necessary for the fibrinogen component and thrombin to react and form enough fibrin to reduce the flow of blood and/or fluid from normal wounded tissue when that dressing is applied to that tissue under the intended conditions of use.
  • the appropriate additional components such as Factor XIII/XIIIa or some other transaminase, may be added to the haemostatic layer(s) without deviating from the spirit of the present invention.
  • the solid dressing of the present invention may contain one or more of these haemostatic layers as well as one or more other layers, such as one or more support layers (e.g. a backing material or an internal support material) and release layers.
  • thrombin is between 0.125 Units/mg of fibrinogen component and 0.080 Units/mg of fibrinogen component.
  • Still other preferred embodiments of the present invention are directed to similar solid dressings wherein the amount of thrombin is (all values being ⁇ 0.0009): 0.250 Units/mg of fibrinogen component; 0.125 Units/mg of fibrinogen component; 0.100 Units/mg of fibrinogen component; 0.080 Units/mg of fibrinogen component; 0.062 Units/mg of fibrinogen component; 0.050 Units/mg of fibrinogen component; and 0.025 Units/mg of fibrinogen component.
  • Another preferred embodiment of the present invention is directed to a method for treating wounded tissue in a mammal, comprising placing a solid dressing of the present invention to wounded tissue and applying sufficient pressure to the dressing for a sufficient time for enough fibrin to form to reduce the loss of blood and/or other fluid from the wound.
  • the haemostatic layer(s) of the solid dressing is formed or cast as a single piece.
  • the haemostatic layer is made or formed into or from a single source, e.g. an aqueous solution containing a mixture of the fibrinogen component and the thrombin.
  • the haemostatic layer(s) is preferably substantially homogeneous throughout.
  • the haemostatic layer(s) of the solid dressing are composed of a plurality of particles, each of which consists essentially of a fibrinogen component and thrombin.
  • the haemostatic layer may also contain a binding agent to facilitate or improve the adherence of the particles to one another and/or to any support layer(s).
  • suitable binding agents include, but are not limited to, sucrose, mannitol, sorbitol, gelatin, maltose, hyaluron and its derivatives, such as hyaluronic acid, povidone, starch, chitosan and its derivatives (e.g. NOCC-chitosan), and cellulose derivatives, such as carboxymethylcellulose, as well as mixtures of two or more thereof.
  • the haemostatic layer(s) of the solid dressing may also optionally contain one or more suitable fillers, such as sucrose, lactose, maltose, silk, fibrin, collagen, albumin, polysorbate (TweenTM), chitin, chitosan and its derivatives, such as NOCC-chitosan, alginic acid and salts thereof, hyaluron and its derivatives, such as hyaluronic acid, cellulose and derivatives thereof, proteoglycans, glycolic acid polymers, lactic acid polymers, glycolic acid/lactic acid co-polymers, and mixtures of two or more thereof.
  • suitable fillers such as sucrose, lactose, maltose, silk, fibrin, collagen, albumin, polysorbate (TweenTM), chitin, chitosan and its derivatives, such as NOCC-chitosan, alginic acid and salts thereof, hyaluron and its derivatives, such as hyalur
  • the haemostatic layer of the solid dressing may also optionally contain one or more suitable solubilizing agents, such as sucrose, dextrose, mannose, trehalose, mannitol, sorbitol, hyaluron and its derivatives, such as hyaluronic acid, albumin, sorbate, polysorbate (TweenTM), sorbitan (SPANTM) and mixtures of two or more thereof.
  • suitable solubilizing agents such as sucrose, dextrose, mannose, trehalose, mannitol, sorbitol, hyaluron and its derivatives, such as hyaluronic acid, albumin, sorbate, polysorbate (TweenTM), sorbitan (SPANTM) and mixtures of two or more thereof.
  • the haemostatic layer of the solid dressing may also optionally contain one or more suitable foaming agents, such as a mixture of a physiologically acceptable acid (e.g. citric acid or acetic acid) and a physiologically suitable base (e.g. sodium bicarbonate or calcium carbonate).
  • suitable foaming agents include, but are not limited to, dry particles containing pressurized gas, such as sugar particles containing carbon dioxide (see, e.g., U.S. Pat. No. 3,012,893) or other physiologically acceptable gases (e.g. Nitrogen or Argon), and pharmacologically acceptable peroxides.
  • the haemostatic layer(s) of the solid dressing may also optionally contain a suitable source of calcium ions, such as calcium chloride, and/or a fibrin cross-linker, such as a transaminase (e.g. Factor XIII/XIIIa) or glutaraldehyde.
  • a suitable source of calcium ions such as calcium chloride
  • a fibrin cross-linker such as a transaminase (e.g. Factor XIII/XIIIa) or glutaraldehyde.
  • the haemostatic layer of the solid dressing is preferably prepared by mixing aqueous solutions of the fibrinogen component and the thrombin under conditions which minimize the activation of the fibrinogen component by the thrombin.
  • the mixture of aqueous solutions is then subjected to a process such as lyophilization or freeze-drying to reduce the moisture content to the desired level, i.e. to a level where the dressing is solid and therefore will not substantially change in shape or form upon standing, wound-facing surface down, at room temperature for 24 hours.
  • Similar processes that achieve the same result such as drying, spray-drying, vacuum drying and vitrification, may also be employed.
  • moisture content refers to the amount freely-available water in the dressing. “Freely-available” means the water is not bound to or complexed with one or more of the non-liquid components of the dressing.
  • the moisture content referenced herein refers to levels determined by procedures substantially similar to the FDA-approved, modified Karl Fischer method (Meyer and Boyd, Analytical Chem., 31:215-219, 1959; May et al., J. Biol. Standardization, 10:249-259, 1982; Centers for Biologics Evaluation and Research, FDA, Docket No. 89D-0140, 83-93; 1990) or by neat infrared spectroscopy. Suitable moisture content(s) for a particular solid dressing may be determined empirically by one skilled in the art depending upon the intended application(s) thereof.
  • higher moisture contents are associated with more flexible solid dressings.
  • solid dressings intended for extremity wounds it may be preferred to have a moisture content of at least 6% and even more preferably in the range of 6% to 44%.
  • lower moisture contents are associated with more rigid solid dressings.
  • solid dressings intended for flat wounds such as wounds to the abdomen or chest, it may be preferred to have a moisture content of less than 6% and even more preferably in the range of 1% to 6%.
  • suitable moisture contents for solid dressings include, but are not limited to, the following (each value being ⁇ 0.9%): less than 53%; less than 44%; less than 28%; less than 24%; less than 16%; less than 12%; less than 6%; less than 5%; less than 4%; less than 3%; less than 2.5%; less than 2%; less than 1.4%; between 0 and 12%, non-inclusive; between 0 and 6%; between 0 and 4%; between 0 and 3%; between 0 and 2%; between 0 and 1%; between 1 and 16%; between 1 and 11%; between 1 and 8%; between 1 and 6%; between 1 and 4%; between 1 and 3%; between 1 and 2%; and between 2 and 4%.
  • the fibrinogen component in the haemostatic layer(s) of the solid dressings may be any suitable fibrinogen known and available to those skilled in the art.
  • the fibrinogen component may also be a functional derivative or metabolite of a fibrinogen, such the fibrinogen ⁇ , ⁇ and/or ⁇ chains, soluble fibrin I or fibrin II, or a mixture of two or more thereof.
  • a specific fibrinogen (or functional derivative or metabolite) for a particular application may be selected empirically by one skilled in the art.
  • the term “fibrinogen” is intended to include mixtures of fibrinogen and small mounts of Factor XIII/Factor XIIIa, or some other such transaminase. Such small amounts are generally recognized by those skilled in the art as usually being found in mammalian fibrinogen after it has been purified according to the methods and techniques presently known and available in the art and typically range from 0.1 to 20 Units/mL.
  • the fibrinogen employed as the fibrinogen component of the solid dressing is a purified fibrinogen suitable for introduction into a mammal.
  • fibrinogen is a part of a mixture of human plasma proteins which include Factor XIII/XIIIa and have been purified to an appropriate level and virally inactivated.
  • a preferred aqueous solution of fibrinogen for preparation of a solid dressing contains around 37.5 mg/mL fibrinogen at a pH of around 7.4 ⁇ 0.1, although a pH in the range of 5.5-8.5 may be acceptable.
  • Suitable fibrinogen for use as the fibrinogen component has been described in the art, e.g. U.S. Pat. No. 5,716,645, and similar materials are commercially available, e.g. from sources such as Sigma-Aldrich, Enzyme Research Laboratories, Haematologic Technologies and Aniara.
  • the fibrinogen component is present in an amount of from about 1.5 to about 13.0 mg ( ⁇ 0.9 mg) of fibrinogen per square centimeter of solid dressing, and more preferably from about 3.0 to about 13.0 mg/cm 2 . Greater or lesser amounts, however, may be employed depending upon the particular application intended for the solid dressing. For example, according to certain embodiments where increased adherence is desired, the fibrinogen component is present in an amount of from about 11.0 to about 13.0 mg ( ⁇ 0.9 mg) of fibrinogen per square centimeter of solid dressing. Likewise, according to certain embodiments which are intended for treating low pressure-containing vessels, lower levels of the fibrinogen component may be employed.
  • the thrombin employed in the haemostatic layer is preferably a lyophilized mixture of human plasma proteins which has been sufficiently purified and virally inactivated for the intended use of the solid dressing.
  • Suitable thrombin is available commercially from sources such as Sigma-Aldrich, Enzyme Research Laboratories, Haematologic Technologies and Biomol International.
  • a particularly preferred aqueous solution of thrombin for preparing a solid dressing contains thrombin at a potency of between 10 and 2000 ⁇ 50 International Units/mL, and more preferred at a potency of 25 ⁇ 2.5 International Units/mL.
  • thrombin may include albumin (generally about 0.1 mg/mL) and glycine (generally about 100 mM ⁇ 0.1 mM).
  • the pH of this particularly preferred aqueous solution of thrombin is generally in the range of 6.5-7.8, and preferably 7.4 ⁇ 0.1, although a pH in the range of 5.5-8.5 may be acceptable.
  • the solid dressing may optionally further comprise one or more support layers.
  • a “support layer” refers to a material that sustains or improves the structural integrity of the solid dressing and/or the fibrin clot formed when such a dressing is applied to wounded tissue.
  • the support layer comprises a backing material on the side of the dressing opposite the side to be applied to wounded tissue.
  • a backing material may be affixed with a physiologically-acceptable adhesive or may be self-adhering (e.g. by having a sufficient surface static charge).
  • the backing material may comprise one or more resorbable materials or one or more non-resorbable materials or mixtures thereof.
  • the backing material is a single resorbable material.
  • the resorbable material may be a proteinaceous substance, such as silk, fibrin, keratin, collagen and/or gelatin.
  • the resorbable material may be a carbohydrate substance, such as alginates, chitin, cellulose, proteoglycans (e.g. poly-N-acetyl glucosamine), hyaluron and its derivatives, such as hyaluronic acid, glycolic acid polymers, lactic acid polymers, or glycolic acid/lactic acid co-polymers.
  • the tesorbable material may also comprise a mixture of proteinaceous substances or a mixture of carbohydrate substances or a mixture of both proteinaceous substances and carbohydrate substances.
  • Specific resorbable material(s) may be selected empirically by those skilled in the art depending upon the intended use of the solid dressing.
  • the resorbable material is a carbohydrate substance.
  • Illustrative examples of particularly preferred resorbable materials include, but are not limited to, the materials sold under the trade names VICRYLTM (a glycolic acid/lactic acid copolymer) and DEXONTM (a glycolic acid polymer).
  • non-resorbable material Any suitable non-resorbable material known and available to those skilled in the art may be employed as the backing material.
  • suitable non-resorbable materials include, but are not limited to, plastics, silicone polymers, gauze, latexes, paper and paper products, and the like.
  • the support layer comprises an internal support material.
  • an internal support material is preferably fully embedded or contained within a haemostatic layer of the solid dressing, although it may be placed between two adjacent haemostatic layers in certain embodiments.
  • the internal support material may be a resorbable material or a non-resorbable material, or a mixture thereof, such as a mixture of two or more resorbable materials or a mixture of two or more non-resorbable materials or a mixture of resorbable material(s) and non-resorbable material(s).
  • the support layer may comprise a front support material on the wound-facing side of the dressing, i.e. the side to be applied to wounded tissue.
  • the front support material may be a resorbable material or a non-resorbable material, or a mixture thereof, such as a mixture of two or more resorbable materials or a mixture of two or more non-resorbable materials or a mixture of resorbable material(s) and non-resorbable material(s).
  • the solid dressing comprises both a backing material and an internal support material in addition to the haemostatic layer(s), i.e. the solid dressing comprises two support layers in addition to the haemostatic layer(s).
  • the solid dressing comprises both a front support material and an internal support material in addition to the haemostatic layer(s).
  • the solid dressing comprises a backing material, a front support material and an internal support material in addition to the haemostatic layer(s).
  • the dry dressings may also optionally further comprise a release layer in addition to the hemostatic layer(s) and support layer(s).
  • a “release layer” refers to a layer containing one or more agents (“release agents”) which promote or facilitate removal of the dry dressing from a mold in which it has been manufactured.
  • sucrose is sucrose
  • suitable release agents include gelatin, mannitol, sorbitol, polysorbate (TweenTM), sorbitan (SPANTM), lactose, maltose, trehalose, hyaluron and its derivatives, such as hyaluronic acid, sorbate, glucose and mixtures of two or more thereof.
  • such one or more release agents may be contained in the hemostatic layer.
  • the various layers of the inventive dressings may be affixed to one another by any suitable means known and available to those skilled in the art.
  • a physiologically-acceptable adhesive may be applied to a backing material (when present), and the haemostatic layer(s) subsequently affixed thereto.
  • the physiologically-acceptable adhesive has a shear strength and/or structure such that the backing material can be separated from the fibrin clot formed by the haemostatic layer after application of the dressing to wounded tissue. In other embodiments, the physiologically-acceptable adhesive has a shear strength and/or structure such that the backing material cannot be separated from the fibrin clot after application of the bandage to wounded tissue.
  • Suitable fibrinogen components and suitable thrombin for the haemostatic layer(s) of the solid dressing may be obtained from any appropriate source known and available to those skilled in the art, including, but not limited to, the following: from commercial vendors, such as Sigma-Aldrich and Enzyme Research Laboratories; by extraction and purification from human or mammalian plasma by any of the methods known and available to those skilled in the art; from supernatants or pastes derived from plasma or recombinant tissue culture, viruses, yeast, bacteria, or the like that contain a gene that expresses a human or mammalian plasma protein which has been introduced according to standard recombinant DNA techniques; and/or from the fluids (e.g. blood, milk, lymph, urine or the like) of transgenic mammals (e.g. goats, sheep, cows) that contain a gene which has been introduced according to standard transgenic techniques and that expresses the desired fibrinogen component and/or desired thrombin.
  • transgenic mammals e.g. goats,
  • the fibrinogen component is a mammalian fibrinogen such as bovine fibrinogen, porcine fibrinogen, ovine fibrinogen, equine fibrinogen, caprine fibrinogen, feline fibrinogen, canine fibrinogen, murine fibrinogen or human fibrinogen.
  • the fibrinogen component is bird fibrinogen or fish fibrinogen.
  • the fibrinogen component is human fibrinogen, human fibrinogen ⁇ chain, human fibrinogen ⁇ chain, human fibrinogen ⁇ chain, human fibrinogen ⁇ chain, human fibrin I, human fibrin II, or a mixture of two or more thereof.
  • the fibrinogen may be recombinantly produced fibrinogen or transgenic fibrinogen.
  • the fibrinogen may also contain small amounts (e.g. _-_% of total protein) of a transaminase, such as Factor XIII/XIIIa.
  • the thrombin is a mammalian thrombin, such as bovine thrombin, porcine thrombin, ovine thrombin, equine thrombin, caprine thrombin, feline thrombin, canine thrombin, murine thrombin and human thrombin.
  • the thrombin is bird thrombin or fish thrombin.
  • the thrombin may be recombinantly produced thrombin or transgenic thrombin.
  • the purity of the fibrinogen component and/or the thrombin for use in the solid dressing will be a purity known to one of ordinary skill in the relevant art to lead to the optimal efficacy and stability of the protein(s).
  • the fibrinogen component and/or the thrombin has been subjected to multiple purification steps, such as precipitation, concentration, diafiltration and affinity chromatography (preferably immunoaffinity chromatography), to remove substances which cause fragmentation, activation and/or degradation of the fibrinogen component and/or the thrombin during manufacture, storage and/or use of the solid dressing.
  • Illustrative examples of such substances that are preferably removed by purification include: protein contaminants, such as inter-alpha trypsin inhibitor and pre-alpha trypsin inhibitor; non-protein contaminants, such as lipids; and mixtures of protein and non-protein contaminants, such as lipoproteins.
  • the amount of the fibrinogen component employed in the solid dressing is preferably selected to optimize both the efficacy and stability thereof. As such, a suitable concentration for a particular application of the solid dressing may be determined empirically by one skilled in the relevant art. According to certain preferred embodiments of the present invention, when the fibrinogen component is human fibrinogen, the amount of fibrinogen employed is between 1.5 mg and 13.0 mg (each ⁇ 0.9 mg) per square centimeter of solid dressing, more preferably between 3.0 mg and 13.0 mg per square centimeter and most preferably between 11.0 mg and 13.0 mg per square centimeter.
  • the fibrinogen component and the thrombin are preferably activated at the time the dressing is applied to the wounded tissue by the endogenous fluids of the patient escaping from the hemorrhaging wound.
  • the fibrinogen component and/or the thrombin may be activated by a suitable, physiologically-acceptable liquid, optionally containing any necessary co-factors and/or enzymes, prior to or during application of the dressing to the wounded tissue.
  • the haemostatic layer(s) may also contain one or more supplements, such as growth factors, drugs, polyclonal and monoclonal antibodies and other compounds.
  • supplements include, but are not limited to, the following: fibrinolysis inhibitors, such as aprotonin, tranexamic acid and epsilon-amino-caproic acid; antibiotics, such as tetracycline and ciprofloxacin, amoxicillin, and metronidazole; anticoagulants, such as activated protein C, heparin, prostacyclins, prostaglandins (particularly (PGI 2 ), leukotrienes, antithrombin III, ADPase, and plasminogen activator; steroids, such as dexamethasone, inhibitors of prostacyclin, prostaglandins, leukotrienes and/or kinins to inhibit inflammation; cardiovascular drugs, such as calcium channel blockers, vasod
  • the ability of the dressings to seal an injured blood vessel was determined by an ex vivo porcine arteriotomy (EVPA) performance test, which was first described in U.S. Pat. No. 6,762,336.
  • the EVPA performance test evaluates the ability of a dressing to stop fluid flow through a hole in a porcine artery. While the procedure described in U.S. Pat. No. 6,762,336 has been shown to be useful for evaluating haemostatic dressings, it failed to replicate faithfully the requirements for success in vivo. More specifically, the procedure disclosed in U.S. Pat. No. 6,762,336 required testing at 37° C., whereas, in the real world, wounds are typically cooler than that.
  • Fibrinogen (Enzyme Research LaboratoriesTM (ERL) lot 3114) was formulated in 100 mM Sodium Chloride, 1.1 mM Calcium Chloride, 10 mM Tris, 10 mM Sodium Citrate, 1.5% Sucrose, Human Serum Albumin (HSA) at a concentration of 80 mg/g of total protein and 15 mg/g total protein of TweenTM 80 (animal source) (Complete Fibrinogen buffer (CFB)). The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. The final pH of the fibrinogen was 7.4 ⁇ 0.1. Once prepared the fibrinogen was placed on ice until use.
  • HSA Human Serum Albumin
  • Thrombin was formulated in 150 mM Sodium Chloride, 40 mM Calcium Chloride, 10 mM Tris and 100 mM L-Lysine with the addition of HSA at 100 ug/ml (Complete Thrombin Buffer (CTB)).
  • CTB Complete Thrombin Buffer
  • the final pH of the thrombin was 7.4 ⁇ 0.1.
  • the thrombin concentrations were adjusted with CFB to produce 12.5 units/mg of Fibrinogen (upon mixing), which corresponded to 3120 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C. Molds were removed from the ⁇ 80° C. freezer and placed on a copper plate that was precooled on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was filled with thrombin. Two ml of fibrinogen and 300 micro liters of thrombin were dispensed simultaneously into each mold. Once the molds were filled they were returned to the ⁇ 80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • the thrombin concentrations were adjusted using CTB to deliver the following amounts 2.5, 0.25, 0.1, 0.05, 0.025, 0.016, 0.0125 and 0.01 units/mg of Fibrinogen (upon mixing), which corresponded to 624, 62.4, 25, 12.5, 6.24, 3.99, 3.12, and 2.5 Units/ml thrombin prior to mixing.
  • Fibrinogen upon mixing
  • the thrombin was placed on ice until use.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C. Molds were then removed from the ⁇ 80° C. freezer and placed on an aluminum plate that was pre-cooled on top of dry ice. Three holes were punched at the top of the mold using an 18 gauge needle.
  • One hole was used for injecting fibrinogen, the second for injecting thrombin, and the third hole served as a vent to release air that was displaced from inside the mold.
  • a pipette was then filled with fibrinogen and a second pipette with thrombin. Simultaneously 0.78 ml of fibrinogen and 0.17 ml of thrombin were injected via these pipettes into each mold.
  • Once filled the molds were placed on top of a pool of liquid nitrogen for thirty seconds and then returned to the ⁇ 80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Backing material was placed into 2.4 ⁇ 2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a ⁇ 80° C. freezer for at least 60 minutes.
  • Fibrinogen (ERL lot 3100) was formulated in CFB. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. The final pH of the fibrinogen was 7.4 ⁇ 0.1. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ⁇ 0.1.
  • the thrombin concentrations were adjusted to deliver the following amounts 0.125, 0.025, 0.0125, 0.00625 and 0.0031 units/mg of Fibrinogen upon mixing, which corresponded to 31.2, 6.24, 3.12, 1.56 and 0.78 Units/ml thrombin prior to mixing.
  • the thrombin was placed on ice until use.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C.
  • the molds were removed from the ⁇ 80° C. freezer and placed on an aluminum plate that that was precooled on top of dry ice.
  • a 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin.
  • the contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the ⁇ 80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Backing material was placed into PVC 2.4 ⁇ 2.4 cm molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a ⁇ 80° C. freezer for at least 60 minutes. A vial containing 3 grams of Fibrinogen (SigmaTM Lot# F-3879) was removed the ⁇ 20° C. freezer and placed at 4° C. for 18 hours. The bottle was then removed from the freezer and allowed to come to room temperature for 60 minutes. To the bottle, 60 ml of 37° C. water was added and allowed to mix for 15 minutes at 37° C.
  • the fibrinogen was dialyzed against incomplete fibrinogen buffer (IFB, which was CFB without HSA and TweenTM) for 4 hours at room temperature. At the end of the four hours HSA was added to a concentration of 80 mg/g of total protein, and TweenTM 80 (animal source) was added to a concentration of 15 mg/g total protein. The final pH of the fibrinogen was 7.4 ⁇ 0.1. The fibrinogen concentration was then adjusted to 37.5 mg/m with CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ⁇ 0.1.
  • the thrombin concentrations were adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.083 and 0.0625 units/mg of Fibrinogen (upon mixing) which corresponded to 624, 62.4, 31.2, 20.8 and 15.6 Units/ml thrombin prior to mixing.
  • Fibrinogen upon mixing
  • the thrombin was placed on ice until use.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C. Molds were removed from the ⁇ 80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice.
  • a 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second 1 ml syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin.
  • the contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the ⁇ 80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Backing material was placed into 2.4 ⁇ 2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the molds and held in place by clips located at each end of the mold, producing closed molds. Once completed the molds were placed in a ⁇ 80° C. freezer for at least 60 minutes.
  • Fibrinogen (ERL lot 3060 was formulated in CFB. The final pH of the fibrinogen was 7.4 ⁇ 0.1. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use.
  • Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ⁇ 0.1.
  • thrombin concentrations were adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.083 and 0.062 units/mg of Fibrinogen (after mixing), which corresponded to 624, 62.4, 31.2, 20.8, and 15.6 Units/ml thrombin (prior to mixing).
  • the thrombin was placed on ice until use.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C. Molds were removed from the ⁇ 80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice.
  • a 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin.
  • the contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the ⁇ 80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Backing material was placed into 2.4 ⁇ 2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the 2.4 ⁇ 2.4 molds and held in place by the use of clips located at each end of the mold to create closed molds. The molds were then placed in a ⁇ 80° C. freezer for at least 60 minutes. A vial containing 3 grams of Fibrinogen (Sigma Lot# F-3879) was removed the ⁇ 20° C. freezer and placed at 4° C. for 18 hours. The bottle was then removed from the freezer and allowed to come to room temperature for 60 minutes. To the bottle, 60 ml of 37° C.
  • Thrombin concentration was adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.1 and 0.083 units/mg of Fibrinogen (upon mixing), which corresponded to 624, 62.4, 31.2, 24.96 and 20.79 Units/ml thrombin (before mixing).
  • Fibrinogen upon mixing
  • 624, 62.4, 31.2, 24.96 and 20.79 Units/ml thrombin before mixing.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C. Molds were removed from the ⁇ 80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice.
  • a 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin.
  • the contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the ⁇ 80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Backing material was placed into 2.4 ⁇ 2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the molds and held in place by the use of clips located at each end of the mold to create closed molds. Once completed, the molds were placed in a ⁇ 80° C. freezer for at least 60 minutes.
  • a vial containing 3 grams of Fibrinogen (SigmaTM Lot# F-3879) was removed from the ⁇ 20° C. freezer and placed at 4° C. for 18 hours. The bottle was then allowed to come to room temperature for 60 minutes. To the bottle, 60 ml of 37° C. water was added and allowed to mix for 20 minutes at 37° C. Once in solution, the fibrinogen was dialyzed against IFB. At the end of the four hours, human serum albumin (HSA) was added to a concentration of 80 mg/g of total protein, and TweenTM 80 (animal source) was added to a concentration of 15 mg/g total protein. The final pH of the fibrinogen was 7.4 ⁇ 0.1. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use.
  • HSA human serum albumin
  • TweenTM 80 (animal source) was added to a concentration of 15 mg/g total protein.
  • the final pH of the fibrinogen was 7.4 ⁇ 0.1
  • Thrombin was formulated in CTB.
  • the final pH of the thrombin was 7.4 ⁇ 0.1.
  • Thrombin was adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.08 and 0.06 units/mg of Fibrinogen (after mixing), which corresponded to 624, 62.4, 31.2, 20.8 and 15.6 Units/ml thrombin (prior to mixing).
  • the thrombin was placed on ice until use.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C. Molds were removed from the ⁇ 80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice.
  • a 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin.
  • the contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the ⁇ 80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Trilayer dressings were produced using the process described in U.S. Pat. No. 6,762,336, using the same sources of fibrinogen and thrombin as utilized to produce the monolithic dressings above.
  • FIGS. 1A and 1B The results of the EVPA and Adherence Assays are shown in FIGS. 1A and 1B , respectively.
  • Dressings produced with between 2.5 to 0.025 Thrombin Units/mg of Fibrinogen were active in both assays, while those with greater or lesser ratios of thrombin to fibrinogen were not. Significantly greater activity was seen over the range of 2.5 to 0.05 Thrombin Units/mg of Fibrinogen. Greatly improved performance was seen between the ranges of 0.25 to 0.062 Thrombin Units/mg of Fibrinogen, while optimum performance was seen between the ranges of 0.125 to 0.08 Thrombin Units/mg of Fibrinogen. This contrasted with the dressings produced using the process described in U.S. Pat. No.
  • Monolithic dressings were manufactured as follows: backing material was cut and placed into each PETG 2.4 ⁇ 2.4 cm mold. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a ⁇ 80° C. freezer for at least 60 minutes.
  • ERL fibrinogen lot 3114 was formulated in CFB.
  • the final pH of the fibrinogen was 7.4 ⁇ 0.1.
  • the fibrinogen concentration was adjusted to 37.5 mg/ml.
  • Thrombin was formulated in CTB.
  • the final pH of the thrombin was 7.4 ⁇ 0.1.
  • the thrombin was adjusted to deliver 0.1 units/mg of Fibrinogen or 25 Units/ml thrombin. Once prepared the thrombin was placed on ice until use.
  • the temperature of the fibrinogen and thrombin prior to dispensing was 4° C. ⁇ 2° C. Molds were removed from the ⁇ 80° C.
  • Trilayer dressings were manufactured as described previously 1 , using the same materials as described above. Subsequently, the dressings were placed under conditions of 100% relative humidity at 37° C. for various times in order to increase their relative moisture content to desired levels. The dressings were evaluated visually and for their handling and other physical characteristics. Following this evaluation, a sample of each of the dressings was tested to determine their moisture content. The remaining dressings were performance tested in the EVPA, Adherence and Weight Held assays.
  • the monolithic dressings were fully functional at very high levels of moisture. As much as 28% moisture was found to retain complete functionality. When the moisture levels rose to 44%, the dressings were still functional, however some of their activity was reduced Higher levels of moisture may also retain some function.
  • the original dressings, at 2.5% moisture content, were not flexible, but had all the other desired properties including appearance, a flat surface, integrity, rapid and uncomplicated hydration and a smooth appearance post hydration. Once the moisture content was increased to 5.8%, the monolithic dressings became flexible, while retaining their functionality and desirable characteristics. They retained their flexibility, without curling or losing their integrity or appearing to form excessive amounts of fibrin prior to hydration.
  • Frozen dressings were placed into a pre-cooled GenesisTM lyophylizer (Virtis, Gardiner, N.Y.). The chamber was sealed and the temperature equilibrated. The chamber was then evacuated and the dressings lyophilized via a primary and secondary drying cycle.
  • Thermometer to monitor temperatures of both water bath and oven
  • EXCLUSION CRITERION The mesh backing must remain over the hole in the artery. If it has shifted during the polymerization and does not completely cover the hole the haemostatic dressing must be excluded.
  • FIG. 2 A diagram of the testing equipment set-up is shown in FIG. 2 . Some additional components, not shown, may be utilized to read out (pressure gauge) or control the pressure within the system as desired.
  • the pressure/time profile to be followed is attained by manually turning the pump on and off while referencing the system pressure as read out by one or more pressure-reading components of the system.
  • the haemostatic dressing is subjectively assessed with regard to adhesion to the artery and formation of a plug in the artery hole. Any variations from the positive control should be noted on the data collection form.
  • Haemostatic dressings that are able to withstand pressures for 3 minutes are considered to have passed the assay.
  • the data collection should be stopped immediately so that the natural decrease in pressure that occurs in the artery once the test is ended isn't included on the graphs. Should the operator fail to stop data collection, these points can be deleted from the data file to avoid confusing the natural pressure decay that occurs post-test with an actual dressing failure. The entire testing period from application of the haemostatic dressing to completion must fall within pre-established criteria. The maximum pressure reached should be recorded on the data collection form.
  • Haemostatic dressings that start leaking saline at any point during testing are considered to have failed the assay.
  • the pressure should be allowed to fall ⁇ 20 mmHg before data collection is stopped so that the failure is easily observed on the graphs.
  • the pressures at which leakage occurred should be recorded on the data collection form. Should the data collection stop in the middle of the experiment due to equipment failure the data can be collected by hand at 5 second intervals until the end of the test or haemostatic dressing failure, whichever happens first.
  • the data points should be recorded on the back of the data collection form, clearly labeled, and entered by hand into the data tables.
  • results must be excluded. If there are leaks from collaterals that can't be fixed either by patching or finger pressure the results must be excluded. If the test fails because of leaks at the O-rings, the results must be excluded. If the mesh backing does not completely cover the hole in the artery, the results must be excluded.
  • Hemostat(s), Porcine artery and haemostatic dressing (usually after completion of the EVPA Assay although it does not need to be performed to do the Adherence Assay).
  • the dressing After application of the dressing without completion of the EVPA Assay, the dressing is ready for the Adherence Assay and Weight Limit Test (if applicable). After application of the dressing and subsequent EVPA Analysis, the artery and syringe system is then disconnected slowly from the pump so that solution does not spray everywhere. The warmed, red saline solution from the EVPA Assay remains in the syringe until the Adherence Assay and Weight Limit Test (if applicable) is completed.
  • the mesh backing must remain over the hole in the artery. If it has shifted during the polymerization and does not completely cover the hole the haemostatic dressing must be excluded.
  • a dressing does not adhere to the artery after application and/or prior to performing the EVPA assay it is given a score of 0 and fails the adherence test. If a dressing receives a score ⁇ 2, the dressing is considered to have failed the Adherence Assay.
  • weights may then be added to the hemostat in an incremental manner until the mesh backing is pulled entirely off of the artery.
  • the maximum weight that the dressing holds is then recorded as a measure of the amount of weight the dressing could hold attached to the artery.
  • Moisture determinations were carried out using a Brinkman Metrohm Moisture Analyzer System.
  • the system contains the following individual components, 774 Oven Sample Processor, 774SC Controller, 836 Titrando, 5 ml and 50 ml 800 Dosino Units and a 801 Stirrer.
  • the system was connected to a computer using the Brinkman Tiamo software for data collection, analysis and storage.
  • the moisture system is set-up and run according to the manufactures recommendations and specifications to measure the moisture content of lyophilized samples using the Karl Fischer method.

Abstract

Disclosed are solid dressings for treated wounded tissue in mammalian patients, such as a human, comprising a haemostatic layer consisting essentially of a fibrinogen component and thrombin, wherein the thrombin is present in an amount between 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component. Also disclosed are methods for treating wounded tissue.

Description

    FIELD OF THE INVENTION
  • The present invention relates to a solid dressing for treating wounded tissue in a mammalian patient, such as a human.
  • BACKGROUND OF THE INVENTION
  • The materials and methods available to stop bleeding in pre-hospital care (gauze dressings, direct pressure, and tourniquets) have, unfortunately, not changed significantly in the past 2000 years. See L. Zimmerman et al., Great Ideas in the History of Surgery (San Francisco, Calif.: Norman Publishing; 1993), 31. Even in trained hands they are not uniformly effective, and the occurrence of excessive bleeding or fatal hemorrhage from an accessible site is not uncommon. See J. M. Rocko et al., J. Trauma 22:635 (1982).
  • Mortality data from Vietnam indicates that 10% of combat deaths were due to uncontrolled extremity hemorrhage. See SAS/STAT Users Guide, 4th ed. (Cary, N.C.: SAS Institute Inc; 1990). Up to one third of the deaths from ex-sanguination during the Vietnam War could have been prevented by the use of effective field hemorrhage control methods. See SAS/STAT Users Guide, 4th ed. (Cary, N.C.: SAS Institute Inc; 1990).
  • Although civilian trauma mortality statistics do not provide exact numbers for pre-hospital deaths from extremity hemorrhage, case and anecdotal reports indicate similar occurrences. See J. M. Rocko et al. These data suggest that a substantial increase in survival can be affected by the pre-hospital use of a simple and effective method of hemorrhage control.
  • There are now in use a number of newer haemostatic agents that have been developed to overcome the deficiencies of traditional gauze bandages. These haemostatic agents include the following:
      • Microporous polysaccharide particles (TraumaDEX®, Medafor Inc., Minneapolis, Minn.);
      • Zeolite (QuikClot®, Z-Medica Corp, Wallington, Conn.);
      • Acetylated poly-N-acetyl glucosamine (Rapid Deployment Hemostat™ (RDH), Marine Polymer Technologies, Danvers, Mass.);
      • Chitosan (HemCon® bandage, HemCon Medical Technologies inc., Portland Oreg.);
      • Liquid Fibrin Sealants (Tisseel VH, Baxter, Deerfield, Ill.)
      • Human fibrinogen and thrombin on equine collagen (TachoComb-S, Hafslund Nycomed Pharma, Linz, Austria);
      • Microdispersed oxidized cellulose (M•Doc™, Alltracel Group, Dublin, Ireland);
      • Propyl gallate (Hemostatin™, Analytical Control Systems Inc., Fishers, Ind.);
      • Epsilon aminocaproic acid and thrombin (Hemarrest™ patch, Clarion Pharmaceuticals, Inc);
      • Purified bovine corium collagen (Avitene® sheets (non-woven web or Avitene Microfibrillar Collagen Hemostat (MCH), Davol, Inc., Cranston, R.I.);
      • Controlled oxidation of regenerated cellulose (Surgicel®, Ethicon Inc., Somerville, N.J.);
      • Aluminum sulfate with an ethyl cellulose coating (Sorbastace Microcaps, Hemostace, LLC, New Orleans, La.);
      • Microporous hydrogel-forming polyacrylamide (BioHemostat, Hemodyne, Inc., Richmond Va.); and
      • Recombinant activated factor VII (NovoSeven®, NovoNordisk Inc., Princeton, N.J.).
        These agents have met with varying degrees of success when used in animal models of traumatic injuries and/or in the field.
  • One such agent is a starch-based haemostatic agent sold under the trade name TraumaDEX™. This product comprises microporous polysaccharide particles that are poured directly into or onto a wound. The particles appear to exert their haemostatic effect by absorbing water from the blood and plasma in the wound, resulting in the accumulation and concentration of clotting factors and platelets. In two studies of a lethal groin wound model, however, this agent showed no meaningful benefit over standard gauze dressings. See McManus et al., Business Briefing: Emergency Medical Review 2005, pp. 76-79 (presently available on-line at www.touchbriefings.com/pdf/1334/Wedmore.pdf).
  • Another particle-based agent is QuickClot™ powder, a zeolite granular haemostatic agent that is poured directly into or onto a wound. The zeolite particles also appear to exert their haemostatic effect through fluid absorption, which cause the accumulation and concentration of clotting factors and platelets. Although this agent has been used successfully in some animal studies, there remains concern about the exothermic process of fluid absorption by the particles. Some studies have shown this reaction to produce temperatures in excess of 143° C. in vitro and in excess of 50° C. in vivo, which is severe enough to cause third-degree burns. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 77. The exothermic reaction of QuikClot™ has also been observed to result in gross and histological tissue changes of unknown clinical significance. Acheson et al., J. Trauma 59:865-874 (2005).
  • Unlike these particle-based agents, the Rapid Deployment Hemostat™ appears to exert its haemostatic effect through red blood cell aggregation, platelet activation, clotting cascade activation and local vasoconstriction. The Rapid Deployment Hemostat™ is an algae-derived dressing composed of poly-N-acetyl-glucosamine. While the original dressing design was effective in reducing minor bleeding, it was necessary to add gauze backing in order to reduce blood loss in swine models of aortic and liver injury. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 78.
  • Another poly-N-acetyl-glucosamine-derived dressing is the HemCon™ Chitosan Bandage, which is a freeze-dried chitosan dressing purportedly designed to optimize the mucoadhesive surface density and structural integrity of the chitosan at the site of the wound. The HemCon™ Chitosan Bandage apparently exerts its haemostatic effects primarily through adhesion to the wound, although there is evidence suggesting it may also enhance platelet function and incorporate red blood cells into the clot it forms on the wound. This bandage has shown improved hemostasis and reduced blood loss in several animal models of arterial hemorrhage, but a marked variability was observed between bandages, including the failure of some due to inadequate adherence to the wound. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 79.
  • Liquid fibrin sealants, such as Tisseel VH, have been used for years as an operating room adjunct for hemorrhage control. See J. L. Garza et al., J. Trauma 30:512-513 (1990); H. B. Kram et al., J. Trauma 30:97-101(1990); M. G. Ochsner et al., J. Trauma 30:884-887 (1990); T. L. Matthew et al., Ann. Thorac. Surg. 50:40-44 (1990); H. Jakob et al., J. Vasc. Surg., 1:171-180 (1984). The first mention of tissue glue used for hemostasis dates back to 1909. See Current Trends in Surgical Tissue Adhesives: Proceedings of the First International Symposium on Surgical Adhesives, M. J. MacPhee et al., eds. (Lancaster, Pa.: Technomic Publishing Co; 1995). Liquid fibrin sealants are typically composed of fibrinogen and thrombin, but may also contain Factor XIII/XIIIa, either as a by-product of fibrinogen purification or as an added ingredient (in certain applications, it is therefore not necessary that Factor XIII/Factor XIIIa be present in the fibrin sealant because there is sufficient Factor XIII/XIIIa, or other transaminase, endogenously present to induce fibrin formation). As liquids, however, these fibrin sealants have not proved useful for treating traumatic injuries in the field.
  • Dry fibrinogen-thrombin dressings having a collagen support (e.g. TachoComb™, TachoComb™ H and TachoSil available from Hafslund Nycomed Pharma, Linz, Austria) are also available for operating room use in many European countries. See U. Schiele et al., Clin. Materials 9:169-177 (1992). While these fibrinogen-thrombin dressings do not require the pre-mixing needed by liquid fibrin sealants, their utility for field applications is limited by a requirement for storage at 4° C. and the necessity for pre-wetting with saline solution prior to application to the wound. These dressings are also not effective against high pressure, high volume bleeding. See Sondeen et al., J. Trauma 54:280-285 (2003).
  • A dry fibrinogen/thrombin dressing for treating wounded tissue is also available from the American Red Cross (ARC). As disclosed in U.S. Pat. No. 6,762,336, this particular dressing is composed of a backing material and a plurality of layers, the outer two of which contain fibrinogen (but no thrombin) while the inner layer contains thrombin and calcium chloride (but no fibrinogen). While this dressing has shown great success in several animal models of hemorrhage, the bandage is fragile, inflexible, and has a tendency to break apart when handled. See McManus et al., Business Briefing: Emergency Medical Review 2005, at 78; Kheirabadi et al., J. Trauma 59:25-35 (2005).
  • Other fibrinogen/thrombin-based dressings have also been proposed. For example, U.S. Pat. No. 4,683,142 discloses a resorptive sheet material for closing and healing wounds which consists of a glycoprotein matrix, such as collagen, containing coagulation proteins, such as fibrinogen and thrombin. U.S. Pat. No. 5,702,715 discloses a reinforced biological sealant composed of separate layers of fibrinogen and thrombin, at least one of which also contains a reinforcement filler such as PEG, PVP, BSA, mannitol, FICOLL, dextran, myo-inositol or sodium chlorate. U.S. Pat. No. 6,056,970 discloses dressings composed of a bioabsorbable polymer, such as hyaluronic acid or carboxymethylcellulose, and a haemostatic composition composed of powdered thrombin and/or powdered fibrinogen. U.S. Pat. No. 7,189,410 discloses a bandage composed of a backing material having thereon: (i) particles of fibrinogen; (ii) particles of thrombin; and (iii) calcium chloride. U.S. Patent Application Publication No. US 2006/0155234 A1 discloses a dressing composed of a backing material and a plurality of fibrinogen layers which have discrete areas of thrombin between them. To date, none of these dressings have been approved for use or are available commercially.
  • Accordingly, there remains a need in the art for a solid dressing that can be used to treat wounded tissue, particularly wounded tissue resulting from traumatic injury in the field.
  • SUMMARY OF THE INVENTION
  • It is therefore an object of the present invention to provide a solid dressing that can treat wounded mammalian tissue, particularly wounded tissue resulting from a traumatic injury. It is further an object of the present invention to provide a method of treating wounded mammalian tissue, particularly human tissue. Other objects, features and advantages of the present invention will be set forth in the detailed description of preferred embodiments that follows, and will in part be apparent from that description and/or may be learned by practice of the present invention. These objects and advantages will be realized and attained by the compositions and methods described in this specification and particularly pointed out in the claims that follow.
  • In accordance with these and other objects, a first embodiment of the present invention is direct to a solid dressing for treating wounded tissue in a mammal comprising at least one haemostatic layer consisting essentially of a fibrinogen component and thrombin, wherein the thrombin is present in an amount between about 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component.
  • Another embodiment is directed to a method of treating wounded tissue using a solid dressing comprising at least one haemostatic layer consisting essentially of a fibrinogen component and thrombin, wherein the thrombin is present in an amount between about 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component.
  • Other embodiments are directed to similar solid dressings wherein the amount of thrombin is between 0.125 Units/mg of fibrinogen component and 0.080 Units/mg of fibrinogen component, and the use of the same for treating wounded tissue.
  • It is to be understood that the foregoing general description and the following detailed description of preferred embodiments are exemplary and explanatory only and are intended to provide further explanation, but not limitation, of the invention as claimed herein.
  • BRIEF DESCRIPTION OF DRAWINGS
  • FIG. 1A and FIG. 1B are graphs depicting the results of the EVPA and Adherence Assays.
  • FIG. 2 is a diagram of the set-up for the EVPA Assay.
  • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.
  • As used herein, use of a singular article such as “a,” “an,” and “the” is not intended to excluded pluralities of the article's object unless the context clearly and unambiguously dictates otherwise.
  • “Patient” as used herein refers to human or animal individuals in need of medical care and/or treatment.
  • “Wound” as used herein refers to any damage to any tissue of a patient which results in the loss of blood from the circulatory system and/or any other fluid from the patient's body. The tissue may be an internal tissue, such as an organ or blood vessel, or an external tissue, such as the skin. The loss of blood may be internal, such as from a ruptured organ, or external, such as from a laceration. A wound may be in a soft tissue, such as an organ, or in hard tissue, such as bone. The damage may have been caused by any agent or source, including traumatic injury, infection or surgical intervention.
  • “Resorbable material” as used herein refers to a material that is broken down spontaneously in and/or by the mammalian body into components which are consumed or eliminated in such a manner as not to interfere significantly with wound healing and/or tissue regeneration, and without causing any significant metabolic disturbance.
  • “Stability” as used herein refers to the retention of those characteristics of a material that determine activity and/or function.
  • “Suitable” as used herein is intended to mean that a material does not adversely affect the stability of the dressings or any component thereof.
  • “Binding agent” as used herein refers to a compound or mixture of compounds that improves the adherence and/or cohesion of the components of the haemostatic layer(s) of the dressings.
  • “Solubilizing agent” as used herein refers to a compound or mixture of compounds that improves the dissolution of a protein or proteins in aqueous solvent.
  • “Filler” as used herein refers to a compound or mixture of compounds that provide bulk and/or porosity to the haemostatic layer(s) of a dressing.
  • “Release agent” as used herein refers to a compound or mixture of compounds that facilitates removal of a dressing from a manufacturing mold.
  • “Foaming agent” as used herein refers to a compound or mixture of compounds that produces gas when hydrated under suitable conditions.
  • “Solid” as used herein is intended to mean that the dressing will not substantially change in shape or form when placed on a rigid surface, wound-facing side down, and then left to stand at room temperature for 24 hours.
  • A first preferred embodiment of the present invention is directed to a solid dressing for treating wounded tissue in a patient which comprises a haemostatic layer consisting essentially of a fibrinogen component and thrombin, wherein the thrombin is present in an amount between 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component.
  • As used herein, “consisting essentially of” is intended to mean that the fibrinogen component and the thrombin are the only necessary and essential ingredients of the haemostatic layer(s) of the solid dressing when it is used as intended to treat wounded tissue. Accordingly, the haemostatic layer may contain other ingredients in addition to the fibrinogen component and the thrombin as desired for a particular application, but these other ingredients are not required for the solid dressing to function as intended under normal conditions, i.e. these other ingredients are not necessary for the fibrinogen component and thrombin to react and form enough fibrin to reduce the flow of blood and/or fluid from normal wounded tissue when that dressing is applied to that tissue under the intended conditions of use. If, however, the conditions of use in a particular situation are not normal, for example the patient is a hemophiliac suffering from Factor XIII deficiency, then the appropriate additional components, such as Factor XIII/XIIIa or some other transaminase, may be added to the haemostatic layer(s) without deviating from the spirit of the present invention. Similarly, the solid dressing of the present invention may contain one or more of these haemostatic layers as well as one or more other layers, such as one or more support layers (e.g. a backing material or an internal support material) and release layers.
  • Other preferred embodiments are directed to similar solid dressings wherein the amount of thrombin is between 0.125 Units/mg of fibrinogen component and 0.080 Units/mg of fibrinogen component. Still other preferred embodiments of the present invention are directed to similar solid dressings wherein the amount of thrombin is (all values being ±0.0009): 0.250 Units/mg of fibrinogen component; 0.125 Units/mg of fibrinogen component; 0.100 Units/mg of fibrinogen component; 0.080 Units/mg of fibrinogen component; 0.062 Units/mg of fibrinogen component; 0.050 Units/mg of fibrinogen component; and 0.025 Units/mg of fibrinogen component.
  • Another preferred embodiment of the present invention is directed to a method for treating wounded tissue in a mammal, comprising placing a solid dressing of the present invention to wounded tissue and applying sufficient pressure to the dressing for a sufficient time for enough fibrin to form to reduce the loss of blood and/or other fluid from the wound.
  • According to certain embodiments of the present invention, the haemostatic layer(s) of the solid dressing is formed or cast as a single piece. According to certain other embodiments of the present invention, the haemostatic layer is made or formed into or from a single source, e.g. an aqueous solution containing a mixture of the fibrinogen component and the thrombin. With each of these embodiments of the present invention, the haemostatic layer(s) is preferably substantially homogeneous throughout.
  • According to other preferred embodiments, the haemostatic layer(s) of the solid dressing are composed of a plurality of particles, each of which consists essentially of a fibrinogen component and thrombin. According to such embodiments, the haemostatic layer may also contain a binding agent to facilitate or improve the adherence of the particles to one another and/or to any support layer(s). Illustrative examples of suitable binding agents include, but are not limited to, sucrose, mannitol, sorbitol, gelatin, maltose, hyaluron and its derivatives, such as hyaluronic acid, povidone, starch, chitosan and its derivatives (e.g. NOCC-chitosan), and cellulose derivatives, such as carboxymethylcellulose, as well as mixtures of two or more thereof.
  • The haemostatic layer(s) of the solid dressing may also optionally contain one or more suitable fillers, such as sucrose, lactose, maltose, silk, fibrin, collagen, albumin, polysorbate (Tween™), chitin, chitosan and its derivatives, such as NOCC-chitosan, alginic acid and salts thereof, hyaluron and its derivatives, such as hyaluronic acid, cellulose and derivatives thereof, proteoglycans, glycolic acid polymers, lactic acid polymers, glycolic acid/lactic acid co-polymers, and mixtures of two or more thereof.
  • The haemostatic layer of the solid dressing may also optionally contain one or more suitable solubilizing agents, such as sucrose, dextrose, mannose, trehalose, mannitol, sorbitol, hyaluron and its derivatives, such as hyaluronic acid, albumin, sorbate, polysorbate (Tween™), sorbitan (SPAN™) and mixtures of two or more thereof.
  • The haemostatic layer of the solid dressing may also optionally contain one or more suitable foaming agents, such as a mixture of a physiologically acceptable acid (e.g. citric acid or acetic acid) and a physiologically suitable base (e.g. sodium bicarbonate or calcium carbonate). Other suitable foaming agents include, but are not limited to, dry particles containing pressurized gas, such as sugar particles containing carbon dioxide (see, e.g., U.S. Pat. No. 3,012,893) or other physiologically acceptable gases (e.g. Nitrogen or Argon), and pharmacologically acceptable peroxides.
  • The haemostatic layer(s) of the solid dressing may also optionally contain a suitable source of calcium ions, such as calcium chloride, and/or a fibrin cross-linker, such as a transaminase (e.g. Factor XIII/XIIIa) or glutaraldehyde.
  • The haemostatic layer of the solid dressing is preferably prepared by mixing aqueous solutions of the fibrinogen component and the thrombin under conditions which minimize the activation of the fibrinogen component by the thrombin. The mixture of aqueous solutions is then subjected to a process such as lyophilization or freeze-drying to reduce the moisture content to the desired level, i.e. to a level where the dressing is solid and therefore will not substantially change in shape or form upon standing, wound-facing surface down, at room temperature for 24 hours. Similar processes that achieve the same result, such as drying, spray-drying, vacuum drying and vitrification, may also be employed.
  • As used herein, “moisture content” refers to the amount freely-available water in the dressing. “Freely-available” means the water is not bound to or complexed with one or more of the non-liquid components of the dressing. The moisture content referenced herein refers to levels determined by procedures substantially similar to the FDA-approved, modified Karl Fischer method (Meyer and Boyd, Analytical Chem., 31:215-219, 1959; May et al., J. Biol. Standardization, 10:249-259, 1982; Centers for Biologics Evaluation and Research, FDA, Docket No. 89D-0140, 83-93; 1990) or by neat infrared spectroscopy. Suitable moisture content(s) for a particular solid dressing may be determined empirically by one skilled in the art depending upon the intended application(s) thereof.
  • For example, in certain embodiments of the present invention, higher moisture contents are associated with more flexible solid dressings. Thus, in solid dressings intended for extremity wounds, it may be preferred to have a moisture content of at least 6% and even more preferably in the range of 6% to 44%.
  • Similarly, in other embodiments of the present invention, lower moisture contents are associated with more rigid solid dressings. Thus, in solid dressings intended for flat wounds, such as wounds to the abdomen or chest, it may be preferred to have a moisture content of less than 6% and even more preferably in the range of 1% to 6%.
  • Accordingly, illustrative examples of suitable moisture contents for solid dressings include, but are not limited to, the following (each value being ±0.9%): less than 53%; less than 44%; less than 28%; less than 24%; less than 16%; less than 12%; less than 6%; less than 5%; less than 4%; less than 3%; less than 2.5%; less than 2%; less than 1.4%; between 0 and 12%, non-inclusive; between 0 and 6%; between 0 and 4%; between 0 and 3%; between 0 and 2%; between 0 and 1%; between 1 and 16%; between 1 and 11%; between 1 and 8%; between 1 and 6%; between 1 and 4%; between 1 and 3%; between 1 and 2%; and between 2 and 4%.
  • The fibrinogen component in the haemostatic layer(s) of the solid dressings may be any suitable fibrinogen known and available to those skilled in the art. The fibrinogen component may also be a functional derivative or metabolite of a fibrinogen, such the fibrinogen α, β and/or γ chains, soluble fibrin I or fibrin II, or a mixture of two or more thereof. A specific fibrinogen (or functional derivative or metabolite) for a particular application may be selected empirically by one skilled in the art. As used herein, the term “fibrinogen” is intended to include mixtures of fibrinogen and small mounts of Factor XIII/Factor XIIIa, or some other such transaminase. Such small amounts are generally recognized by those skilled in the art as usually being found in mammalian fibrinogen after it has been purified according to the methods and techniques presently known and available in the art and typically range from 0.1 to 20 Units/mL.
  • Preferably, the fibrinogen employed as the fibrinogen component of the solid dressing is a purified fibrinogen suitable for introduction into a mammal. Typically, such fibrinogen is a part of a mixture of human plasma proteins which include Factor XIII/XIIIa and have been purified to an appropriate level and virally inactivated. A preferred aqueous solution of fibrinogen for preparation of a solid dressing contains around 37.5 mg/mL fibrinogen at a pH of around 7.4±0.1, although a pH in the range of 5.5-8.5 may be acceptable. Suitable fibrinogen for use as the fibrinogen component has been described in the art, e.g. U.S. Pat. No. 5,716,645, and similar materials are commercially available, e.g. from sources such as Sigma-Aldrich, Enzyme Research Laboratories, Haematologic Technologies and Aniara.
  • Preferably, the fibrinogen component is present in an amount of from about 1.5 to about 13.0 mg (±0.9 mg) of fibrinogen per square centimeter of solid dressing, and more preferably from about 3.0 to about 13.0 mg/cm2. Greater or lesser amounts, however, may be employed depending upon the particular application intended for the solid dressing. For example, according to certain embodiments where increased adherence is desired, the fibrinogen component is present in an amount of from about 11.0 to about 13.0 mg (±0.9 mg) of fibrinogen per square centimeter of solid dressing. Likewise, according to certain embodiments which are intended for treating low pressure-containing vessels, lower levels of the fibrinogen component may be employed.
  • While any suitable mammalian thrombin may be used in a solid dressing, the thrombin employed in the haemostatic layer is preferably a lyophilized mixture of human plasma proteins which has been sufficiently purified and virally inactivated for the intended use of the solid dressing. Suitable thrombin is available commercially from sources such as Sigma-Aldrich, Enzyme Research Laboratories, Haematologic Technologies and Biomol International. A particularly preferred aqueous solution of thrombin for preparing a solid dressing contains thrombin at a potency of between 10 and 2000±50 International Units/mL, and more preferred at a potency of 25±2.5 International Units/mL. Other constituents may include albumin (generally about 0.1 mg/mL) and glycine (generally about 100 mM±0.1 mM). The pH of this particularly preferred aqueous solution of thrombin is generally in the range of 6.5-7.8, and preferably 7.4±0.1, although a pH in the range of 5.5-8.5 may be acceptable.
  • In addition to the haemostatic layer(s), the solid dressing may optionally further comprise one or more support layers. As used herein, a “support layer” refers to a material that sustains or improves the structural integrity of the solid dressing and/or the fibrin clot formed when such a dressing is applied to wounded tissue.
  • According to certain preferred embodiments of the present invention the support layer comprises a backing material on the side of the dressing opposite the side to be applied to wounded tissue. Such a backing material may be affixed with a physiologically-acceptable adhesive or may be self-adhering (e.g. by having a sufficient surface static charge). The backing material may comprise one or more resorbable materials or one or more non-resorbable materials or mixtures thereof. Preferably, the backing material is a single resorbable material.
  • Any suitable resorbable material known and available to those skilled in the art may be employed in the present invention. For example, the resorbable material may be a proteinaceous substance, such as silk, fibrin, keratin, collagen and/or gelatin. Alternatively, the resorbable material may be a carbohydrate substance, such as alginates, chitin, cellulose, proteoglycans (e.g. poly-N-acetyl glucosamine), hyaluron and its derivatives, such as hyaluronic acid, glycolic acid polymers, lactic acid polymers, or glycolic acid/lactic acid co-polymers. The tesorbable material may also comprise a mixture of proteinaceous substances or a mixture of carbohydrate substances or a mixture of both proteinaceous substances and carbohydrate substances. Specific resorbable material(s) may be selected empirically by those skilled in the art depending upon the intended use of the solid dressing.
  • According to certain preferred embodiments of the present invention, the resorbable material is a carbohydrate substance. Illustrative examples of particularly preferred resorbable materials include, but are not limited to, the materials sold under the trade names VICRYL™ (a glycolic acid/lactic acid copolymer) and DEXON™ (a glycolic acid polymer).
  • Any suitable non-resorbable material known and available to those skilled in the art may be employed as the backing material. Illustrative examples of suitable non-resorbable materials include, but are not limited to, plastics, silicone polymers, gauze, latexes, paper and paper products, and the like.
  • According to other preferred embodiments, the support layer comprises an internal support material. Such an internal support material is preferably fully embedded or contained within a haemostatic layer of the solid dressing, although it may be placed between two adjacent haemostatic layers in certain embodiments. As with the backing material, the internal support material may be a resorbable material or a non-resorbable material, or a mixture thereof, such as a mixture of two or more resorbable materials or a mixture of two or more non-resorbable materials or a mixture of resorbable material(s) and non-resorbable material(s).
  • According to still other preferred embodiments, the support layer may comprise a front support material on the wound-facing side of the dressing, i.e. the side to be applied to wounded tissue. As with the backing material and the internal support material, the front support material may be a resorbable material or a non-resorbable material, or a mixture thereof, such as a mixture of two or more resorbable materials or a mixture of two or more non-resorbable materials or a mixture of resorbable material(s) and non-resorbable material(s).
  • According to still other preferred embodiments, the solid dressing comprises both a backing material and an internal support material in addition to the haemostatic layer(s), i.e. the solid dressing comprises two support layers in addition to the haemostatic layer(s). According to still other preferred embodiments, the solid dressing comprises both a front support material and an internal support material in addition to the haemostatic layer(s). According to still other preferred embodiments, the solid dressing comprises a backing material, a front support material and an internal support material in addition to the haemostatic layer(s).
  • According to certain embodiments of the present invention, particularly where the dry dressing is manufactured using a mold, the dry dressings may also optionally further comprise a release layer in addition to the hemostatic layer(s) and support layer(s). As used herein, a “release layer” refers to a layer containing one or more agents (“release agents”) which promote or facilitate removal of the dry dressing from a mold in which it has been manufactured. A preferred such agent is sucrose, but other suitable release agents include gelatin, mannitol, sorbitol, polysorbate (Tween™), sorbitan (SPAN™), lactose, maltose, trehalose, hyaluron and its derivatives, such as hyaluronic acid, sorbate, glucose and mixtures of two or more thereof. Alternatively, such one or more release agents may be contained in the hemostatic layer.
  • The various layers of the inventive dressings may be affixed to one another by any suitable means known and available to those skilled in the art. For example, a physiologically-acceptable adhesive may be applied to a backing material (when present), and the haemostatic layer(s) subsequently affixed thereto.
  • In certain embodiments of the present invention, the physiologically-acceptable adhesive has a shear strength and/or structure such that the backing material can be separated from the fibrin clot formed by the haemostatic layer after application of the dressing to wounded tissue. In other embodiments, the physiologically-acceptable adhesive has a shear strength and/or structure such that the backing material cannot be separated from the fibrin clot after application of the bandage to wounded tissue.
  • Suitable fibrinogen components and suitable thrombin for the haemostatic layer(s) of the solid dressing may be obtained from any appropriate source known and available to those skilled in the art, including, but not limited to, the following: from commercial vendors, such as Sigma-Aldrich and Enzyme Research Laboratories; by extraction and purification from human or mammalian plasma by any of the methods known and available to those skilled in the art; from supernatants or pastes derived from plasma or recombinant tissue culture, viruses, yeast, bacteria, or the like that contain a gene that expresses a human or mammalian plasma protein which has been introduced according to standard recombinant DNA techniques; and/or from the fluids (e.g. blood, milk, lymph, urine or the like) of transgenic mammals (e.g. goats, sheep, cows) that contain a gene which has been introduced according to standard transgenic techniques and that expresses the desired fibrinogen component and/or desired thrombin.
  • According to certain preferred embodiments of the present invention, the fibrinogen component is a mammalian fibrinogen such as bovine fibrinogen, porcine fibrinogen, ovine fibrinogen, equine fibrinogen, caprine fibrinogen, feline fibrinogen, canine fibrinogen, murine fibrinogen or human fibrinogen. According to other embodiments, the fibrinogen component is bird fibrinogen or fish fibrinogen. According to still other embodiments, the fibrinogen component is human fibrinogen, human fibrinogen α chain, human fibrinogen β chain, human fibrinogen γ chain, human fibrin I, human fibrin II, or a mixture of two or more thereof. According to any of these embodiments, the fibrinogen may be recombinantly produced fibrinogen or transgenic fibrinogen. As noted above, the fibrinogen may also contain small amounts (e.g. _-_% of total protein) of a transaminase, such as Factor XIII/XIIIa.
  • According to certain preferred embodiments of the present invention, the thrombin is a mammalian thrombin, such as bovine thrombin, porcine thrombin, ovine thrombin, equine thrombin, caprine thrombin, feline thrombin, canine thrombin, murine thrombin and human thrombin. According to other embodiments, the thrombin is bird thrombin or fish thrombin. According to any of these embodiments, the thrombin may be recombinantly produced thrombin or transgenic thrombin.
  • As a general proposition, the purity of the fibrinogen component and/or the thrombin for use in the solid dressing will be a purity known to one of ordinary skill in the relevant art to lead to the optimal efficacy and stability of the protein(s). Preferably, the fibrinogen component and/or the thrombin has been subjected to multiple purification steps, such as precipitation, concentration, diafiltration and affinity chromatography (preferably immunoaffinity chromatography), to remove substances which cause fragmentation, activation and/or degradation of the fibrinogen component and/or the thrombin during manufacture, storage and/or use of the solid dressing. Illustrative examples of such substances that are preferably removed by purification include: protein contaminants, such as inter-alpha trypsin inhibitor and pre-alpha trypsin inhibitor; non-protein contaminants, such as lipids; and mixtures of protein and non-protein contaminants, such as lipoproteins.
  • The amount of the fibrinogen component employed in the solid dressing is preferably selected to optimize both the efficacy and stability thereof. As such, a suitable concentration for a particular application of the solid dressing may be determined empirically by one skilled in the relevant art. According to certain preferred embodiments of the present invention, when the fibrinogen component is human fibrinogen, the amount of fibrinogen employed is between 1.5 mg and 13.0 mg (each ±0.9 mg) per square centimeter of solid dressing, more preferably between 3.0 mg and 13.0 mg per square centimeter and most preferably between 11.0 mg and 13.0 mg per square centimeter.
  • During use of the solid dressing, the fibrinogen component and the thrombin are preferably activated at the time the dressing is applied to the wounded tissue by the endogenous fluids of the patient escaping from the hemorrhaging wound. Alternatively, in situations where fluid loss from the wounded tissue is insufficient to provide adequate hydration of the protein layers, the fibrinogen component and/or the thrombin may be activated by a suitable, physiologically-acceptable liquid, optionally containing any necessary co-factors and/or enzymes, prior to or during application of the dressing to the wounded tissue.
  • In some embodiments of the present invention, the haemostatic layer(s) may also contain one or more supplements, such as growth factors, drugs, polyclonal and monoclonal antibodies and other compounds. Illustrative examples of such supplements include, but are not limited to, the following: fibrinolysis inhibitors, such as aprotonin, tranexamic acid and epsilon-amino-caproic acid; antibiotics, such as tetracycline and ciprofloxacin, amoxicillin, and metronidazole; anticoagulants, such as activated protein C, heparin, prostacyclins, prostaglandins (particularly (PGI2), leukotrienes, antithrombin III, ADPase, and plasminogen activator; steroids, such as dexamethasone, inhibitors of prostacyclin, prostaglandins, leukotrienes and/or kinins to inhibit inflammation; cardiovascular drugs, such as calcium channel blockers, vasodilators and vasoconstrictors; chemoattractants; local anesthetics such as bupivacaine; and antiproliferative/antitumor drugs such as 5-fluorouracil (5-FU), taxol and/or taxotere; antivirals, such as gangcyclovir, zidovudine, amantidine, vidarabine, ribaravin, trifluridine, acyclovir, dideoxyuridine and antibodies to viral components or gene products; cytokines, such as alpha- or beta- or gamma-Interferon, alpha- or beta-tumor necrosis factor, and interleukins; colony stimulating factors; erythropoietin; antifungals, such as diflucan, ketaconizole and nystatin; antiparasitic gents, such as pentamidine; anti-inflammatory agents, such as alpha-1-anti-trypsin and alpha-1-antichymotrypsin; anesthetics, such as bupivacaine; analgesics; antiseptics; hormones; vitamins and other nutritional supplements; glycoproteins; fibronectin; peptides and proteins; carbohydrates (both simple and/or complex); proteoglycans; antiangiogenins; antigens; lipids or liposomes; oligonucleotides (sense and/or antisense DNA and/or RNA); and gene therapy reagents. In other embodiments of the present invention, the backing layer and/or the internal support layer, if present, may contain one or more supplements. According to certain preferred embodiments of the present invention, the therapeutic supplement is present in an amount greater than its solubility limit in fibrin.
  • The following examples are illustrative only and are not intended to limit the scope of the invention as defined by the appended claims. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.
  • EXAMPLES
  • The ability of the dressings to seal an injured blood vessel was determined by an ex vivo porcine arteriotomy (EVPA) performance test, which was first described in U.S. Pat. No. 6,762,336. The EVPA performance test evaluates the ability of a dressing to stop fluid flow through a hole in a porcine artery. While the procedure described in U.S. Pat. No. 6,762,336 has been shown to be useful for evaluating haemostatic dressings, it failed to replicate faithfully the requirements for success in vivo. More specifically, the procedure disclosed in U.S. Pat. No. 6,762,336 required testing at 37° C., whereas, in the real world, wounds are typically cooler than that. This decreased temperature can significantly reduce the rate of fibrin formation and its haemostatic efficacy in trauma victims. See, e.g., Acheson et al., J. Trauma 59:865-874 (2005). The test in U.S. Pat. No. 6,762,336 also failed to require a high degree of adherence of the dressing to the injured tissue. A failure mode in which fibrin forms but the dressing fails to attach tightly to the tissue would, therefore, not be detected by this test. Additionally, the pressure utilized in the procedure (200 mHg) may be exceeded during therapy for some trauma patients. The overall result of this is that numerous animal tests, typically involving small animals (such as rats and rabbits), must be conducted to accurately predict dressing performance in large animal, realistic trauma studies and in the clinical environment.
  • In order to minimize the amount of time and the number of animal studies required to develop the present invention, an improved ex vivo testing procedure was developed. To accomplish this, the basic conditions under which the dressing test was conducted were changed, and the severity of the test parameters was increased to include testing at lower temperatures (i.e. 29-33° C. vs. 37° C., representing the real physiologic challenge at realistic wound temperatures (Acheson et al., J. Trauma 59:865-874 (2005)), higher pressures (i.e. 250 mmHg vs. 200 mmHg), a longer test period (3 minutes vs. 2 minutes) and larger sized arterial injuries (U.S. Pat. No. 6,762,336 used an 18 gauge needle puncture, whereas the revised procedure used puncture holes ranging from 2.8 mm to 4 mm×6 mm).
  • In addition, a new test was derived to directly measure adherence of the dressing to the injured tissue. Both these tests showed greatly improved stringency and are thus capable of surpassing the previous ex vivo test and replacing many in vivo tests for efficacy.
  • The following is a list of acronyms used in the Examples below:
    • CFB: Complete Fibrinogen Buffer (100 mM Sodium Chloride, 1.1 mM Calcium Chloride, 10 mM Tris, 10 mM Sodium Citrate, 1.5% Sucrose, Human Serum Albumin (80 mg/g of total protein) and Tween™ 80 (animal source) 15 mg/g total protein)
    • CTB: Complete Thrombin Buffer (150 mM Sodium Chloride, 40 mM Calcium Chloride, 10 mM Tris and 100 mM L-Lysine with the addition of HSA at 100 ug/ml)
    • ERL: Enzyme Research Laboratories
    • EVPA: Ex Vivo Porcine Arteriotomy
    • FD: Inventive haemostatic dressing
    • HSA: Human Serum Albumin
    • HD: A “sandwich” fibrin sealant haemostatic dressing as disclosed in U.S. Pat. No. 6,762,336
    • IFB: Incomplete Fibrinogen Buffer; CFB without HSA and Tween
    • PETG: Glycol-modified Polyethlylenetetrapthalate
    • PPG: Polypropylene
    • PVC: Poly vinyl chloride
    • TRIS: trishydroxymethylaminomethane (2-amino-2-hydroxymethyl-1,3-propanediol)
    Example 1
  • Backing material (DEXON™) was placed into 2.4×2.4 cm PETG molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a −80° C. freezer for at least 60 minutes.
  • Fibrinogen (Enzyme Research Laboratories™ (ERL) lot 3114) was formulated in 100 mM Sodium Chloride, 1.1 mM Calcium Chloride, 10 mM Tris, 10 mM Sodium Citrate, 1.5% Sucrose, Human Serum Albumin (HSA) at a concentration of 80 mg/g of total protein and 15 mg/g total protein of Tween™ 80 (animal source) (Complete Fibrinogen buffer (CFB)). The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. The final pH of the fibrinogen was 7.4±0.1. Once prepared the fibrinogen was placed on ice until use.
  • Thrombin was formulated in 150 mM Sodium Chloride, 40 mM Calcium Chloride, 10 mM Tris and 100 mM L-Lysine with the addition of HSA at 100 ug/ml (Complete Thrombin Buffer (CTB)). The final pH of the thrombin was 7.4±0.1. The thrombin concentrations were adjusted with CFB to produce 12.5 units/mg of Fibrinogen (upon mixing), which corresponded to 3120 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use.
  • The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. Molds were removed from the −80° C. freezer and placed on a copper plate that was precooled on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was filled with thrombin. Two ml of fibrinogen and 300 micro liters of thrombin were dispensed simultaneously into each mold. Once the molds were filled they were returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Example 2
  • Backing material was placed into each 1.5×1.5 cm PVC molds. Fifteen microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was fitted on top of the 1.5×1.5 molds and held in place. This formed a closed mold. The molds were then placed in a −80° C. freezer for at least 60 minutes. Fibrinogen (ERL lot 3100) was formulated in CFB. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. The final pH of the fibrinogen was 7.4±0.1. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4±0.1. The thrombin concentrations were adjusted using CTB to deliver the following amounts 2.5, 0.25, 0.1, 0.05, 0.025, 0.016, 0.0125 and 0.01 units/mg of Fibrinogen (upon mixing), which corresponded to 624, 62.4, 25, 12.5, 6.24, 3.99, 3.12, and 2.5 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. Molds were then removed from the −80° C. freezer and placed on an aluminum plate that was pre-cooled on top of dry ice. Three holes were punched at the top of the mold using an 18 gauge needle. One hole was used for injecting fibrinogen, the second for injecting thrombin, and the third hole served as a vent to release air that was displaced from inside the mold. A pipette was then filled with fibrinogen and a second pipette with thrombin. Simultaneously 0.78 ml of fibrinogen and 0.17 ml of thrombin were injected via these pipettes into each mold. Once filled the molds were placed on top of a pool of liquid nitrogen for thirty seconds and then returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Example 3
  • Backing material was placed into 2.4×2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a −80° C. freezer for at least 60 minutes. Fibrinogen (ERL lot 3100) was formulated in CFB. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. The final pH of the fibrinogen was 7.4±0.1. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4±0.1. Using CTB, the thrombin concentrations were adjusted to deliver the following amounts 0.125, 0.025, 0.0125, 0.00625 and 0.0031 units/mg of Fibrinogen upon mixing, which corresponded to 31.2, 6.24, 3.12, 1.56 and 0.78 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. The molds were removed from the −80° C. freezer and placed on an aluminum plate that that was precooled on top of dry ice. A 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Example 4
  • Backing material was placed into PVC 2.4×2.4 cm molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a −80° C. freezer for at least 60 minutes. A vial containing 3 grams of Fibrinogen (Sigma™ Lot# F-3879) was removed the −20° C. freezer and placed at 4° C. for 18 hours. The bottle was then removed from the freezer and allowed to come to room temperature for 60 minutes. To the bottle, 60 ml of 37° C. water was added and allowed to mix for 15 minutes at 37° C. Once in solution the fibrinogen was dialyzed against incomplete fibrinogen buffer (IFB, which was CFB without HSA and Tween™) for 4 hours at room temperature. At the end of the four hours HSA was added to a concentration of 80 mg/g of total protein, and Tween™ 80 (animal source) was added to a concentration of 15 mg/g total protein. The final pH of the fibrinogen was 7.4±0.1. The fibrinogen concentration was then adjusted to 37.5 mg/m with CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4±0.1. Using CTB, the thrombin concentrations were adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.083 and 0.0625 units/mg of Fibrinogen (upon mixing) which corresponded to 624, 62.4, 31.2, 20.8 and 15.6 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. Molds were removed from the −80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice. A 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second 1 ml syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Example 5
  • Backing material was placed into 2.4×2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the molds and held in place by clips located at each end of the mold, producing closed molds. Once completed the molds were placed in a −80° C. freezer for at least 60 minutes. Fibrinogen (ERL lot 3060 was formulated in CFB. The final pH of the fibrinogen was 7.4±0.1. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4±0.1. Using CTB, thrombin concentrations were adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.083 and 0.062 units/mg of Fibrinogen (after mixing), which corresponded to 624, 62.4, 31.2, 20.8, and 15.6 Units/ml thrombin (prior to mixing). Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. Molds were removed from the −80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice. A 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Example 6
  • Backing material was placed into 2.4×2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the 2.4×2.4 molds and held in place by the use of clips located at each end of the mold to create closed molds. The molds were then placed in a −80° C. freezer for at least 60 minutes. A vial containing 3 grams of Fibrinogen (Sigma Lot# F-3879) was removed the −20° C. freezer and placed at 4° C. for 18 hours. The bottle was then removed from the freezer and allowed to come to room temperature for 60 minutes. To the bottle, 60 ml of 37° C. water was added and allowed to mix for 15 minutes at 37° C. Once in solution the fibrinogen was dialyzed against IFB. At the end of the four hours HSA was added to a concentration of 80 mg/g of total protein, and Tween™ 80 (animal source) was added to a concentration of 15 mg/g total protein. The final pH of the fibrinogen was 7.4±0.1. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4±0.1. Thrombin concentration was adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.1 and 0.083 units/mg of Fibrinogen (upon mixing), which corresponded to 624, 62.4, 31.2, 24.96 and 20.79 Units/ml thrombin (before mixing). Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. Molds were removed from the −80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice. A 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Example 7
  • Backing material was placed into 2.4×2.4 cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the molds and held in place by the use of clips located at each end of the mold to create closed molds. Once completed, the molds were placed in a −80° C. freezer for at least 60 minutes.
  • A vial containing 3 grams of Fibrinogen (Sigma™ Lot# F-3879) was removed from the −20° C. freezer and placed at 4° C. for 18 hours. The bottle was then allowed to come to room temperature for 60 minutes. To the bottle, 60 ml of 37° C. water was added and allowed to mix for 20 minutes at 37° C. Once in solution, the fibrinogen was dialyzed against IFB. At the end of the four hours, human serum albumin (HSA) was added to a concentration of 80 mg/g of total protein, and Tween™ 80 (animal source) was added to a concentration of 15 mg/g total protein. The final pH of the fibrinogen was 7.4±0.1. The fibrinogen concentration was adjusted to 37.5 mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use.
  • Thrombin was formulated in CTB. The final pH of the thrombin was 7.4±0.1. Thrombin was adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.08 and 0.06 units/mg of Fibrinogen (after mixing), which corresponded to 624, 62.4, 31.2, 20.8 and 15.6 Units/ml thrombin (prior to mixing). Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. Molds were removed from the −80° C. freezer and placed on an aluminum plate that was that was precooled on top of dry ice. A 3 ml syringe fitted with an 18 gauge needle was filled with 2 ml of fibrinogen and a second, 1 ml, syringe fitted with a 22 gauge needle was filled with 0.3 ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below.
  • Trilayer (Sandwich) Dressings
  • Trilayer dressings were produced using the process described in U.S. Pat. No. 6,762,336, using the same sources of fibrinogen and thrombin as utilized to produce the monolithic dressings above.
  • Results
  • The results of the EVPA and Adherence Assays are shown in FIGS. 1A and 1B, respectively.
  • Conclusions:
  • Dressings produced with between 2.5 to 0.025 Thrombin Units/mg of Fibrinogen were active in both assays, while those with greater or lesser ratios of thrombin to fibrinogen were not. Significantly greater activity was seen over the range of 2.5 to 0.05 Thrombin Units/mg of Fibrinogen. Greatly improved performance was seen between the ranges of 0.25 to 0.062 Thrombin Units/mg of Fibrinogen, while optimum performance was seen between the ranges of 0.125 to 0.08 Thrombin Units/mg of Fibrinogen. This contrasted with the dressings produced using the process described in U.S. Pat. No. 6,762,336 which reached full performance at 12.5 Thrombin Units/mg of Fibrinogen, with unacceptable performance occurring as the thrombin concentration was diminished below 12.5 Thrombin Units/mg of Fibrinogen, with essentially no activity remaining at 1.4 Thrombin Units/mg of Fibrinogen. This difference in both the limits of performance and the optimum levels is all the more profound given that the performance of the Trilayer dressings from U.S. Pat. No. 6,762,336 was decreased by the use of decreasing amounts of thrombin, while the dressing described herein showed an increased activity over this range.
  • Example 8
  • Monolithic dressings were manufactured as follows: backing material was cut and placed into each PETG 2.4×2.4 cm mold. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a −80° C. freezer for at least 60 minutes.
  • For all dressings, ERL fibrinogen lot 3114 was formulated in CFB. The final pH of the fibrinogen was 7.4±0.1. The fibrinogen concentration was adjusted to 37.5 mg/ml. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4±0.1. The thrombin was adjusted to deliver 0.1 units/mg of Fibrinogen or 25 Units/ml thrombin. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4° C.±2° C. Molds were removed from the −80° C. freezer and placed on a copper plate that was placed on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was filled with thrombin. Simultaneously 2 ml of fibrinogen and 300 micro liters of thrombin were dispensed into each mold. Once the molds were filled they were returned to the −80° C. freezer for at least two hours before being placed into the freeze dryer. Dressings were then lyophilized as described above. Once complete the dressings were stored in low moisture transmission foil bags containing 5 grams of desiccant.
  • Trilayer dressings were manufactured as described previously1, using the same materials as described above. Subsequently, the dressings were placed under conditions of 100% relative humidity at 37° C. for various times in order to increase their relative moisture content to desired levels. The dressings were evaluated visually and for their handling and other physical characteristics. Following this evaluation, a sample of each of the dressings was tested to determine their moisture content. The remaining dressings were performance tested in the EVPA, Adherence and Weight Held assays.
  • Results
  • The results of the assays are given in the Tables below:
    TABLE 1
    Performance Data of Inventive Solid Dressings
    Exposure Time
    to 100%
    Humidity Peel Test Weight Held
    @ 37° C. % EVPA # Adherence (g) (mean ±
    (minutes) Moisture Pass/Total (±Std. Dev.) Std. Dev.)
    0 2.5 2/2 4.0 ± 0 148 ± 28.3
    1 5.8 2/2   3.5 ± 0.71 123 ± 7.1 
    15 16 2/2   2.5 ± .71 108 ± 14.1
    45 24 2/2 4.0 ± 0 168 ± 0  
    60 28 2/2 4.0 ± 0 273 ± 7.1 
    225 44 2/2   2 ± 0  58 ± 14.1
    1200 52 ND ND ND
  • TABLE 2
    Performance Data for Tri-layer Dressings
    Exposure Time
    to 100%
    Humidity
    @ 37° C. % EVPA # Peel Test Weight Held
    (minutes) Moisture Pass/Total Adherence (g) (mean)
    0 3 1/1 2.0 78
    15 22 1/1 2.0 78
    60 33.7 0/1 0.5 28
  • TABLE 3
    Integrity and Handling Characteristics of Inventive Solid Dressings
    Exposure Time During Hydration
    to 100% Force
    Humidity Prior To Hydration Required After
    @ 37° C. Surface Speed of for Hydration
    (minutes) Appearance Curling Integrity Flexible Hydration Hydration Appearance
    0 Normal No Excellent No Normal No Normal
    (Smooth, No (No cracks or
    “skin”) flaking off)
    1 Normal Excellent Yes
    (Smooth, No (No cracks or
    “skin”) flaking off)
    15 Normal Excellent
    (Smooth, No (No cracks or
    “skin”) flaking off)
    45 Normal Excellent
    (Smooth, No (No cracks or
    “skin”) flaking off)
    60 Normal Slight Excellent
    (Smooth, No (No cracks or
    “skin”) flaking off)
    225 Normal Yes Excellent
    (Smooth, No (No cracks or
    “skin”) flaking off)
    1200 Normal Curling Excellent n/d n/d Mottled and
    (Smooth, No up on (No cracks or lumpy
    “skin”) itself flaking off)
  • TABLE 4
    Integrity and Handling Characteristics of Trilayer Dressings
    Exposure Time During Hydration
    to 100% Force
    Humidity Prior To Hydration Required After
    @ 37° C. Surface Speed of for Hydration
    (minutes) Appearance Curling Integrity Flexibility Hydration Hydration Appearance
    0 Normal No Good. Some No Normal No Normal
    delamination
    15 Irregular No Good. Some Yes Slow No Mottled
    delamination
    60 Skinned Yes Good. Some Yes Very Slow Yes Very
    delamination Mottled and
    lumpy

    Conclusions:
  • The monolithic dressings were fully functional at very high levels of moisture. As much as 28% moisture was found to retain complete functionality. When the moisture levels rose to 44%, the dressings were still functional, however some of their activity was reduced Higher levels of moisture may also retain some function. The original dressings, at 2.5% moisture content, were not flexible, but had all the other desired properties including appearance, a flat surface, integrity, rapid and uncomplicated hydration and a smooth appearance post hydration. Once the moisture content was increased to 5.8%, the monolithic dressings became flexible, while retaining their functionality and desirable characteristics. They retained their flexibility, without curling or losing their integrity or appearing to form excessive amounts of fibrin prior to hydration.
  • This contrasted with the tri-layer dressings, which began to lose their desirable characteristics upon the addition of moisture, and lost them entirely by the time moisture had increased to 33%.
  • Lyophilization Procedure
  • Frozen dressings were placed into a pre-cooled Genesis™ lyophylizer (Virtis, Gardiner, N.Y.). The chamber was sealed and the temperature equilibrated. The chamber was then evacuated and the dressings lyophilized via a primary and secondary drying cycle.
  • EVPA Performance Testing
  • Equipment and Supplies:
      • In-line high pressure transducer (Ashcroft Duralife™ or equivalent)
      • Peristaltic pump (Pharmacia Biotech™, Model P-1 or equivalent)
      • Voltmeter (Craftsman™ Professional Model 82324 or equivalent)
      • Computer equipped with software for recording pressure or voltage information
      • Tygon™ tubing (assorted sizes) with attachments
      • Water bath (Baxter Durabath™ or equivalent), preset to 37° C.
      • Incubation chamber (VWR™, Model 1400G or equivalent), preset to 37° C.
  • Thermometer to monitor temperatures of both water bath and oven
      • Assorted forceps, hemostats, and scissors
      • 10 cc. and 20 cc. syringes with an approximately 0.6 cm hole drilled in center and smaller hole drilled through both syringe and plunger. This hole, drilled into the end of the syringe, will be used to keep the plunger drawn back and stationary.
      • O-rings (size 10 and 13)
      • Plastic Shields to fit the 10 cc and 20 cc syringes (approximately 3.5 cm in length)
      • P-1000 Pipetman™ with tips
      • Sphygmomanometer with neonatal size cuff and bladder
      • Programmable Logic Controller (PLC) to control the pumps to maintain the desired pressure profile (Optional. Manual control may be used if desired.)
  • 1. Materials and Chemicals
      • Porcine descending aortas (Pel-Freez Biologicals™, Catalog #59402-2 or equivalent)
      • Cyanoacrylate glue (Vetbond™, 3M or equivalent)
      • 18-gauge needle(s)
      • 0.9% Saline, maintained at 37° C.
      • Red food coloring
      • Vascular Punch(es), 2.8 mm or other
      • Plastic Wrap
  • 2. Artery Cleaning and Storage
      • 1. Store arteries at −20° C. until used.
      • 2. Thaw arteries at 37° C. in H2O bath.
      • 3. Clean fat and connective tissue from exterior surface of artery.
      • 4. Cut the arteries into ˜5 cm segments.
      • 5. The arteries may be refrozen to −20° C. and stored until use.
  • 3. Artery Preparation for Assay
      • 1. Turn the artery inside-out so that the smooth, interior wall is facing outwards.
      • 2. Stretch a size 13 O-ring over a 20 cc syringe or a size 10 O-ring over a 10 cc syringe with an approximately 0.6 cm (0.25 in) hole drilled into one side.
      • 3. Pull the artery onto the syringe, taking care not to tear the artery or have a too loose fit. The artery should fit snugly to the syringe. Slide another O-ring of the same size onto the bottom of the syringe
      • 4. Carefully pull both O-rings over the ends of the artery. The distance between the O-rings should be at least 3.5 cm
      • 5. Using the blade of some surgical scissors, gently scrape the surface of the artery in order to roughen the surface of the artery.
      • 6. Use a 18-gauge needle to poke a hole through the artery over the site of the hole in the syringe barrel (see note above)
      • 7. The tip of the biopsy punch is inserted through the hole in the artery. Depress the punch's plunger to make an open hole in the artery. Repeat a couple of times to ensure that the hole is open and free of connective tissue.
      • 8. Patch holes left by collateral arteries. Generally this is done by cutting a patch from a latex glove and gluing it over the hole with cyanoacrylate glue. Allow the glue to cure for at least 10 minutes.
      • 9. Place the artery in the warmed, moistened container and place in the incubation chamber. Allow the arteries to warm for at least 30 minutes.
  • 4. Solution and Equipment Preparation
      • 1. Check to see that the water bath and incubation chamber are maintained at 29-33° C.
      • 2. Make sure that there is sufficient 0.9% saline in the pump's reservoir for completion of the day's assays. Add more if needed.
      • 3. Place 0.9% saline and 0.9% saline with a few drops of red food coloring added into containers in a water bath so that the solutions will be warmed prior to performing the assay.
      • 4. Prepare the container for warming the arteries in the incubation chamber by lining with KimWipes™ and adding a small amount of water to keep the arteries moist.
      • 5. Check the tubing for air bubbles. If bubbles exist, turn on the pump and allow the 0.9% saline to flow until all bubbles are removed.
  • 5. Application of the Dressing
      • 1. Open the haemostatic dressing pouch and remove haemostatic dressing
      • 2. Place the haemostatic dressing, mesh backing side UP, over the hole in the artery
      • 3. Slowly wet the haemostatic dressing with an amount of saline appropriate for the article being tested
        • NOTE: A standard (13-15 mg/cm2 of fibrinogen) 2.4×2.4 cm haemostatic dressing should be wet with 800 μl of saline or other blood substitute. The amount of saline used can be adjusted depending on the requirements of the particular experiment being performed; however, any changes should be noted on the data collection forms.
        • NOTE: Wet the haemostatic dressing drop wise with 0.9% saline warmed to 29-33° C. or other blood substitute, taking care to keep the saline from running off the edges. Any obvious differences in wetting characteristics from the positive control should be noted on data collection forms.
      • 4. Place the shield gently onto the haemostatic dressing, taking care that it lies flat between the O-rings. Press lightly to secure in place
      • 5. Wrap the artery and haemostatic dressing with plastic wrap
      • 6. Wrap with blood pressure cuff, taking care that the bladder is adjacent to the haemostatic dressing.
      • 7. Pump up the bladder to 100-120 mmHg, and monitor the pressure and pump again if it falls below 100 mmHg. Maintain pressure for 5 minutes.
        • NOTE: Time and pressure can be altered according to the requirements of the experiment; changes from the standard conditions should be noted on the data collection forms.
      • 8. After polymerization, carefully unwrap the artery and note the condition of the haemostatic dressing. Any variation from the positive control should be noted on the data collection form.
  • EXCLUSION CRITERION: The mesh backing must remain over the hole in the artery. If it has shifted during the polymerization and does not completely cover the hole the haemostatic dressing must be excluded.
  • Testing Procedure
  • 1. Diagram of Testing Equipment Set-Up
  • A diagram of the testing equipment set-up is shown in FIG. 2. Some additional components, not shown, may be utilized to read out (pressure gauge) or control the pressure within the system as desired.
  • 1. Equipment and Artery Assembly
  • Fill the artery and syringe with red 0.9% saline warmed to 37° C., taking care to minimize the amount of air bubbles within the syringe & artery. Filling the artery with the opening uppermost can assist with this. Attach the artery and syringe to the testing apparatus, making sure that there are as few air bubbles in the tubing as possible. The peristaltic pump should be calibrated so that it delivers approximately 3 ml/min. If available, the PLC should be operated according to a pre-determined range of pressures and hold times as appropriate for the article being tested. If under manual control, the pressure/time profile to be followed is attained by manually turning the pump on and off while referencing the system pressure as read out by one or more pressure-reading components of the system. Following the conclusion of testing, the haemostatic dressing is subjectively assessed with regard to adhesion to the artery and formation of a plug in the artery hole. Any variations from the positive control should be noted on the data collection form.
  • Success Criteria
  • Haemostatic dressings that are able to withstand pressures for 3 minutes are considered to have passed the assay. When a haemostatic dressing has successfully passed the assay the data collection should be stopped immediately so that the natural decrease in pressure that occurs in the artery once the test is ended isn't included on the graphs. Should the operator fail to stop data collection, these points can be deleted from the data file to avoid confusing the natural pressure decay that occurs post-test with an actual dressing failure. The entire testing period from application of the haemostatic dressing to completion must fall within pre-established criteria. The maximum pressure reached should be recorded on the data collection form.
      • NOTE: Typical challenge is 250 mmHg for three minutes in one step, but that may be altered based on the article being tested. Changes from the standard procedure should be noted on the data collection forms.
        Failure Criteria
  • Haemostatic dressings that start leaking saline at any point during testing are considered to have failed the assay.
      • NOTE: Build failures that are caused by artery swelling can be ignored and the test continued or re-started (as long as the total testing time doesn't fall beyond the established limit).
  • When leakage does occur, the pressure should be allowed to fall ˜20 mmHg before data collection is stopped so that the failure is easily observed on the graphs. The pressures at which leakage occurred should be recorded on the data collection form. Should the data collection stop in the middle of the experiment due to equipment failure the data can be collected by hand at 5 second intervals until the end of the test or haemostatic dressing failure, whichever happens first. The data points should be recorded on the back of the data collection form, clearly labeled, and entered by hand into the data tables.
  • Exclusion Criteria
  • If the total testing period exceeds the maximum allowed for that procedure, regardless of cause, results must be excluded. If there are leaks from collaterals that can't be fixed either by patching or finger pressure the results must be excluded. If the test fails because of leaks at the O-rings, the results must be excluded. If the mesh backing does not completely cover the hole in the artery, the results must be excluded.
  • Adherence Performance Testing
  • 1. Equipment and Supplies
  • Hemostat(s), Porcine artery and haemostatic dressing (usually after completion of the EVPA Assay although it does not need to be performed to do the Adherence Assay).
  • 1. Preparation of the Artery+Dressing
  • After application of the dressing without completion of the EVPA Assay, the dressing is ready for the Adherence Assay and Weight Limit Test (if applicable). After application of the dressing and subsequent EVPA Analysis, the artery and syringe system is then disconnected slowly from the pump so that solution does not spray everywhere. The warmed, red saline solution from the EVPA Assay remains in the syringe until the Adherence Assay and Weight Limit Test (if applicable) is completed.
  • Performance of the Adherence Assay
  • 1. After preparation of the artery and dressing (with or without EVPA analysis), gently lift the corner of the mesh and attach a hemostat of known mass to the corner.
      • NOTE: If the FD developed a channel leak during the performance of the EVPA Assay, test the adherence on the opposite of the haemostatic dressing to obtain a more accurate assessment of the overall adherence.
  • 2. Gently let go of the hemostat, taking care not to allow the hemostat to drop or twist. Turn the syringe so that the hemostat is near the top and allow the hemostat to peel back the dressing as far as the dressing will permit. This usually occurs within 10 seconds. After the hemostat has stopped peeling back the dressing, rate the adherence of the bandage according to the following scale:
    Dressing Performance Score Amount of Adherence
    4 90+%
    3 75-90%
    2 50-75%
    1 ˜50%
    0.5 Only the plug holds the hemostat
    0 No adherence

    Exclusion Criteria
  • The mesh backing must remain over the hole in the artery. If it has shifted during the polymerization and does not completely cover the hole the haemostatic dressing must be excluded.
  • Success Criteria
  • Dressings that are given an adherence score of 3 are considered to have passed the assay.
  • Failure Criteria
  • If a dressing does not adhere to the artery after application and/or prior to performing the EVPA assay it is given a score of 0 and fails the adherence test. If a dressing receives a score ≦2, the dressing is considered to have failed the Adherence Assay.
  • Weight Held Performance Assay
  • After the initial scoring of the “Adherence Test”, weights may then be added to the hemostat in an incremental manner until the mesh backing is pulled entirely off of the artery. The maximum weight that the dressing holds is then recorded as a measure of the amount of weight the dressing could hold attached to the artery.
  • Moisture Assay
  • Moisture determinations were carried out using a Brinkman Metrohm Moisture Analyzer System. The system contains the following individual components, 774 Oven Sample Processor, 774SC Controller, 836 Titrando, 5 ml and 50 ml 800 Dosino Units and a 801 Stirrer. The system was connected to a computer using the Brinkman Tiamo software for data collection, analysis and storage. The moisture system is set-up and run according to the manufactures recommendations and specifications to measure the moisture content of lyophilized samples using the Karl Fischer method.
  • All components were turned on and allowed to reach operating temperature prior to use. Lactose and water were run as standards and to calibrate the instrument. Once the machine was successfully calibrated, samples were prepared as follows. Dressing pieces weighing at least 30 mg were placed into vials and capped. The vials were placed in the 774 Oven Sample Processor in numerical order, and one empty capped vial is placed in the conditioning space. The machine was then run to determine the moisture content (residual moisture) in the controls and samples.

Claims (40)

1. A solid dressing for treating wounded tissue in a mammal comprising at least one haemostatic layer consisting essentially of thrombin and a fibrinogen component, wherein said thrombin is present in an amount between about 0.250 Units/mg of fibrinogen component and 0.062 Units/mg of fibrinogen component.
2. The solid dressing of claim 1, further comprising at least one support layer.
3. The solid dressing of claim 2, wherein said support layer comprises a backing material.
4. The solid dressing of claim 2, wherein said support layer comprises an internal support material.
5. The solid dressing of claim 2, wherein said support layer comprises a resorbable material.
6. The solid dressing of claim 2, wherein said support layer comprises a non-resorbable material.
7. The solid dressing of claim 6, wherein said non-resorbable material is selected from the group consisting of silicone polymers, gauze and latexes.
8. The solid dressing of claim 3, further comprising at least physiologically acceptable adhesive between said haemostatic layer and said backing layer.
9. The solid dressing of claim 5, wherein said resorbable material is selected from the group consisting of proteinaceous materials and carbohydrate substances.
10. The solid dressing of claim 9, wherein said proteinaceous material is at least one substance selected from the group consisting of keratin, silk, fibrin, collagen and gelatin.
11. The solid dressing of claim 9, wherein said carbohydrate substance is selected from the group consisting of alginic acid and salts thereof, chitin, chitosan, hyaluron, hyaluronic acid, cellulose, n-acetyl glucosamine, proteoglycans, glycolic acid polymers, lactic acid polymers, glycolic acid/lactic acid co-polymers and mixtures of two or more thereof.
12. The solid dressing of claim 1, wherein said haemostatic layer also contains a fibrin cross-linker and/or a source of calcium ions.
13. The solid dressing of claim 1, wherein said haemostatic layer also contains one or more of the following: at least one filler, at least one solubilizing agent, at least one foaming agent and at least one release agent.
14. The solid dressing of claim 13, wherein said filler is selected from the group consisting of sucrose, lactose, maltose, keratin, silk, fibrin, collagen, gelatin, albumin, polysorbate, chitin, chitosan, hyaluron, hyaluronic acid, alginic acid and salts thereof, cellulose, proteoglycans, glycolic acid polymers, lactic acid polymers, glycolic acid/lactic acid co-polymers, and mixtures of two or more thereof.
15. The solid dressing of claim 13, wherein said solubilizing agent is selected from the group consisting of sucrose, lactose, maltose, dextrose, mannose, trehalose, mannitol, sorbitol, hyaluron, hyaluronic acid, albumin, sorbate, polysorbate, and mixtures of two or more thereof.
16. The solid dressing of claim 13, wherein said release agent is selected from the group consisting of gelatin, hyaluton, hyalruonic acid, mannitol, sorbitol, polysorbate, sorbitan, lactose, maltose, trehalose, sorbate, glucose and mixtures of two or more thereof.
17. The solid dressing of claim 13, wherein said foaming agent is selected from the group consisting of mixtures of sodium bicarbonate/citric acid, sodium bicarbonate/acetic acid, calcium carbonate/citric acid and calcium carbonate/acetic acid.
18. The solid dressing of claim 1, wherein said haemostatic layer also contains at least one therapeutic supplement selected from the group consisting of antibiotics, anticoagulants, steroids, cardiovascular drugs, growth factors, antibodies (poly and mono), chemoattractants, anesthetics, antiproliferatives/antitumor agents, antivirals, cytokines, colony stimulating factors, antifungals, antiparasitics, antimflammatories, antiseptics, hormones, vitamins, glycoproteins, fibronectin, peptides, proteins, carbohydrates, proteoglycans, antiangiogenins, antigens, nucleotides, lipids, liposomes, fibrinolysis inhibitors and gene therapy reagents.
19. The solid dressing of claim 1, wherein said haemostatic layer is made from a single aqueous solution containing a mixture of said fibrinogen component and said thrombin.
20. The solid dressing of claim 1, wherein said haemostatic layer is cast as a single piece.
21. The solid dressing of claim 1, wherein said haemostatic layer is substantially homogeneous throughout.
22. The solid dressing of claim 1, wherein said haemostatic layer is composed of a plurality of particles, each of said particles consisting essentially of fibrinogen and thrombin.
23. The solid dressing of claim 22, wherein said haemostatic layer further contains at least one binding agent in an amount effective to improve the adherence of said particles to one another.
24. The solid dressing of claim 25, wherein said binding agent is selected from the group consisting of sucrose, mannitol, sorbitol, gelatin, maltose, povidone, hyaluron, hyaluronic acid, chitosan and carboxymethylcellulose.
25. The solid dressing of claim 1, wherein said haemostatic layer is a monolith.
26. The solid dressing of claim 1, wherein said haemostatic layer has been lyophilized.
27. The solid dressing of claim 1, wherein said haemostatic layer has moisture content of at least 6%.
28. The solid dressing of claim 1, wherein said haemostatic layer has moisture content of less than 6%.
29. The solid dressing of claim 1, wherein said fibrinogen component is a mammalian fibrinogen.
30. The solid dressing of claim 29, wherein said mammalian fibrinogen is selected from the group consisting of bovine fibrinogen, porcine fibrinogen, ovine fibrinogen, equine fibrinogen, caprine fibrinogen, feline fibrinogen, canine fibrinogen, murine fibrinogen and human fibrinogen.
31. The solid dressing of claim 1, wherein said fibrinogen component is selected from the group consisting of bird fibrinogen and fish fibrinogen.
32. The solid dressing of claim 1, wherein said fibrinogen component is selected from the group consisting of human fibrinogen, human fibrin I, human fibrin II, human fibrinogen a chain, human fibrinogen β chain, human fibrinogen γ chain, and mixtures of two or more thereof.
33. The solid dressing of claim 29, 31 or 32, wherein said fibrinogen is selected from the group consisting of recombinantly produced fibrinogen and transgenic fibrinogen.
34. The solid dressing of claim 29, wherein said mammalian fibrinogen is present in an amount between 1.5 mg/cm2 of the wound-facing surface of said dressing and 13.0 mg/cm2 of the wound-facing surface of said dressing.
35. The solid dressing of claim 1, wherein said thrombin is mammalian thrombin.
36. The solid dressing of claim 35, wherein said mammalian thrombin is selected from the group consisting of bovine thrombin, porcine thrombin, ovine thrombin, equine thrombin, caprine thrombin, feline thrombin, canine thrombin, murine thrombin and human thrombin.
37. The solid dressing of claim 1, wherein said thrombin is selected from the group consisting of bird thrombin and fish thrombin.
38. The solid dressing of claim 35 or 37, wherein said thrombin is selected from the group consisting of recombinantly produced thrombin and transgenic thrombin.
39. The solid dressing of claim 19, wherein said therapeutic supplement is present in an amount equal to or greater than its solubility limit in fibrin.
40. A method of treating wounded tissue in a mammal, comprising placing a solid dressing of claim 1 to said wounded tissue and applying sufficient pressure to said dressing for a sufficient time for enough fibrin to form to reduce the loss of blood and/or other fluid from said wounded tissue.
US11/882,879 2006-08-04 2007-08-06 Solid dressing for treating wounded tissue Abandoned US20080033333A1 (en)

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US11/882,879 US20080033333A1 (en) 2006-08-04 2007-08-06 Solid dressing for treating wounded tissue
US13/364,837 US20120150087A1 (en) 2006-08-04 2012-02-02 Solid dressing for treating wounded tissue
US14/583,002 US20150118284A1 (en) 2006-08-04 2014-12-24 Solid dressing for treating wounded tissue
US15/088,438 US20160213806A1 (en) 2006-08-04 2016-04-01 Solid dressing for treating wounded tissue
US15/605,660 US20180117210A1 (en) 2006-08-04 2017-05-25 Solid dressing for treating wounded tissue and processes for mixing fibrinogen and thrombin while preserving fibrin-forming ability, compositions produced by these processes, and the use thereof
US16/289,535 US20200000957A1 (en) 2006-08-04 2019-02-28 Solid dressing for treating wounded tissue and processes for mixing fibrinogen and thrombin while preserving fibrin-forming ability, compositions produced by these processes, and the use thereof

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US11/882,879 US20080033333A1 (en) 2006-08-04 2007-08-06 Solid dressing for treating wounded tissue

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US11/882,874 Abandoned US20080033331A1 (en) 2006-08-04 2007-08-06 Solid dressing for treating wounded tissue
US11/882,872 Active US8445009B2 (en) 2006-08-04 2007-08-06 Processes for the production of solid dressings for treating wounded tissue
US13/363,489 Abandoned US20120148658A1 (en) 2006-08-04 2012-02-01 Solid dressing for treating wounded tissue
US13/364,762 Abandoned US20120148659A1 (en) 2006-08-04 2012-02-02 Solid dressing for treating wounded tissue
US13/364,837 Abandoned US20120150087A1 (en) 2006-08-04 2012-02-02 Solid dressing for treating wounded tissue
US14/583,002 Abandoned US20150118284A1 (en) 2006-08-04 2014-12-24 Solid dressing for treating wounded tissue
US14/599,519 Abandoned US20150132363A1 (en) 2006-08-04 2015-01-18 Solid dressing for treating wounded tissue
US14/746,482 Abandoned US20150283288A1 (en) 2006-08-04 2015-06-22 Solid dressing for treating wounded tissue
US15/088,438 Abandoned US20160213806A1 (en) 2006-08-04 2016-04-01 Solid dressing for treating wounded tissue
US15/208,591 Abandoned US20160317355A1 (en) 2006-08-04 2016-07-12 Solid dressing for treating wounded tissue
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US13/363,489 Abandoned US20120148658A1 (en) 2006-08-04 2012-02-01 Solid dressing for treating wounded tissue
US13/364,762 Abandoned US20120148659A1 (en) 2006-08-04 2012-02-02 Solid dressing for treating wounded tissue
US13/364,837 Abandoned US20120150087A1 (en) 2006-08-04 2012-02-02 Solid dressing for treating wounded tissue
US14/583,002 Abandoned US20150118284A1 (en) 2006-08-04 2014-12-24 Solid dressing for treating wounded tissue
US14/599,519 Abandoned US20150132363A1 (en) 2006-08-04 2015-01-18 Solid dressing for treating wounded tissue
US14/746,482 Abandoned US20150283288A1 (en) 2006-08-04 2015-06-22 Solid dressing for treating wounded tissue
US15/088,438 Abandoned US20160213806A1 (en) 2006-08-04 2016-04-01 Solid dressing for treating wounded tissue
US15/208,591 Abandoned US20160317355A1 (en) 2006-08-04 2016-07-12 Solid dressing for treating wounded tissue
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070219489A1 (en) * 2006-03-14 2007-09-20 Johnson Royce W Method for percutaneously administering reduced pressure treatment using balloon dissection
US20070219497A1 (en) * 2006-02-06 2007-09-20 Johnson Royce W System and method for purging a reduced pressure apparatus during the administration of reduced pressure treatment
US20080033324A1 (en) * 2006-03-14 2008-02-07 Cornet Douglas A System for administering reduced pressure treatment having a manifold with a primary flow passage and a blockage prevention member
US20080154233A1 (en) * 2006-12-20 2008-06-26 Zimmer Orthobiologics, Inc. Apparatus for delivering a biocompatible material to a surgical site and method of using same
US20090012629A1 (en) * 2007-04-12 2009-01-08 Isto Technologies, Inc. Compositions and methods for tissue repair
US20090157017A1 (en) * 2006-03-14 2009-06-18 Archel Ambrosio Bioresorbable foaming tissue dressing
US20100168688A1 (en) * 2006-03-14 2010-07-01 Carl Joseph Santora Manifolds, systems, and methods for administering reduced pressure to a subcutaneous tissue site
US20100172889A1 (en) * 2008-12-05 2010-07-08 Catchmark Jeffrey M Degradable biomolecule compositions
US20120070477A1 (en) * 2009-05-28 2012-03-22 Profibrix B.V. Dry powder fibrin sealant
US20120177718A1 (en) * 2009-06-11 2012-07-12 The Chemo-Sero-Therapeutic Research Institute Wound-covering material
US8273369B2 (en) 2010-05-17 2012-09-25 Ethicon, Inc. Reinforced absorbable synthetic matrix for hemostatic applications
US8480757B2 (en) 2005-08-26 2013-07-09 Zimmer, Inc. Implants and methods for repair, replacement and treatment of disease
US8497121B2 (en) 2006-12-20 2013-07-30 Zimmer Orthobiologics, Inc. Method of obtaining viable small tissue particles and use for tissue repair
US8518433B2 (en) 2003-12-11 2013-08-27 Zimmer, Inc. Method of treating an osteochondral defect
US20140081192A1 (en) * 2011-03-21 2014-03-20 KET Kunststoff-und Elaststoff-und Elasttechnik GmbH Liegau-Augustustutusbad Primary dressing for moist wound healing, and method for producing said primary dressing
CN104189941A (en) * 2014-09-03 2014-12-10 北京化工大学 Chitosan gel haemostatic material and preparation method thereof
US9089584B2 (en) 2009-05-28 2015-07-28 Profibrix B.V. Treatment of tissue adhesion
US9561300B2 (en) 2011-09-26 2017-02-07 Yes, Inc. Hemostatic compositions and dressings for bleeding
US10137222B2 (en) 2015-03-27 2018-11-27 3M Innovative Properties Company Fibrin composition, method and wound articles
US10167447B2 (en) 2012-12-21 2019-01-01 Zimmer, Inc. Supports and methods for promoting integration of cartilage tissue explants
US10202517B2 (en) 2013-07-26 2019-02-12 The Penn State Research Foundation Polymer compositions and coatings
US10940233B2 (en) 2016-10-05 2021-03-09 3M Innovative Properties Company Fibrinogen composition, method and wound articles
US11827754B2 (en) 2016-10-05 2023-11-28 3M Innovative Properties Company Fibrin composition comprising carrier material, method and wound articles

Families Citing this family (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160106883A1 (en) * 2014-10-15 2016-04-21 Stb, Ltd. Processes For Mixing Fibrinogen and Thrombin Under Conditions That Minimize Fibrin Formation While Preserving Fibrin-forming Ability, Compositions Produced by These Processes, and the Use Thereof
WO2008019126A2 (en) * 2006-08-04 2008-02-14 Stb Lifesaving Technologies, Inc. Process for production of solid wound dressing
US7776022B2 (en) * 2007-03-19 2010-08-17 Hemcon Medical Technologies Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma
US8449520B2 (en) * 2007-03-19 2013-05-28 HemCon Medical Technologies Inc. Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma
US20090223080A1 (en) * 2007-03-19 2009-09-10 Hemcon Medical Technologies, Inc. Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma
US20090107001A1 (en) * 2007-03-19 2009-04-30 Hemcon Medical Technologies, Inc. Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma
US9174042B2 (en) * 2007-05-25 2015-11-03 Empi, Inc. Wound healing electrode set
BRPI0817544A2 (en) 2007-10-10 2017-05-02 Univ Wake Forest Health Sciences apparatus for treating damaged spinal cord tissue
GB2461019B (en) * 2008-04-25 2013-06-05 Medtrade Products Ltd Haemostatic material
AU2015202402B2 (en) * 2008-04-25 2016-06-16 Medtrade Products Limited Haemostatic material
CN102159139A (en) * 2008-07-18 2011-08-17 韦克福里斯特大学健康科学院 Apparatus and method for cardiac tissue modulation by topical application of vacuum to minimize cell death and damage
US20110150765A1 (en) * 2008-10-31 2011-06-23 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Frozen compositions and methods for piercing a substrate
US9050070B2 (en) * 2008-10-31 2015-06-09 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8518031B2 (en) * 2008-10-31 2013-08-27 The Invention Science Fund I, Llc Systems, devices and methods for making or administering frozen particles
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US8721583B2 (en) * 2008-10-31 2014-05-13 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
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US8603494B2 (en) * 2008-10-31 2013-12-10 The Invention Science Fund I, Llc Compositions and methods for administering compartmentalized frozen particles
US9827205B2 (en) * 2008-12-12 2017-11-28 Mallinckrodt Pharma Ip Trading D.A.C. Dry powder fibrin sealant
ITPI20090066A1 (en) * 2009-05-26 2010-11-27 Consiglio Nazionale Ricerche METHOD TO PRODUCE A DEVICE APPLICABLE TO BIOLOGICAL FABRICS, IN PARTICULAR A PATCH TO TREAT DAMAGED FABRICS, AND DEVICE OBTAINED WITH THIS METHOD
US9271925B2 (en) * 2013-03-11 2016-03-01 Bioinspire Technologies, Inc. Multi-layer biodegradable device having adjustable drug release profile
EP2477617B1 (en) * 2009-09-18 2018-01-31 Bioinspire Technologies Inc. Free-standing biodegradable patch
US20110086236A1 (en) * 2009-10-13 2011-04-14 The Penn State Research Foundation Composites containing polypeptides attached to polysaccharides and molecules
CA2787883C (en) 2010-01-28 2019-02-19 Erez Ilan Method for improved fibrin sealing
CN103096944A (en) * 2010-07-20 2013-05-08 一般财团法人化学及血清疗法研究所 Sheet preparation for tissue adhesion
WO2012067620A1 (en) * 2010-11-18 2012-05-24 The United States Of America, As Represented By The Secretary Of The Army, On Behalf Of William Beaumont Army Spray foam splint
CA2828910C (en) * 2011-03-18 2019-04-23 Marine Polymer Technologies, Inc. Methods and apparatus for a manual radial artery compression device
RS56367B1 (en) 2011-05-24 2017-12-29 Takeda As Rolled collagen carrier
RU2013155713A (en) * 2011-07-06 2015-08-20 Профибрикс Бв COMPOSITIONS FOR TREATMENT OF THE RAS
US20130224712A1 (en) * 2012-02-24 2013-08-29 Bradford L. Day Medical training kits and methods to simulate treatment of uncontrolled hemorrhage
CA2865349C (en) 2012-03-06 2021-07-06 Ferrosan Medical Devices A/S Pressurized container containing haemostatic paste
WO2013185776A1 (en) 2012-06-12 2013-12-19 Ferrosan Medical Devices A/S Dry haemostatic composition
EP2687224A1 (en) * 2012-07-19 2014-01-22 Tissue Med Biosciences Forschungs- und Entwicklungsgesellschaft mbH Medicament for wound treatment
US9214077B2 (en) * 2012-10-08 2015-12-15 Location Labs, Inc. Bio-powered locator device
WO2014066724A1 (en) 2012-10-26 2014-05-01 Wake Forest University Health Sciences Novel nanofiber-based graft for heart valve replacement and methods of using the same
WO2014145255A1 (en) * 2013-03-15 2014-09-18 Stb, Ltd. Compositions having absorbable materials, methods, and applicators for sealing injuries
US20140271600A1 (en) * 2013-03-15 2014-09-18 Gabrielle Giet Non-cellular bandage, method of using the same, and method of preparing the same
CN105555299B (en) * 2013-04-22 2023-03-28 西兰丁姆医疗公司 Fibrinogen-based tissue adhesive patch
US11071805B2 (en) 2013-04-22 2021-07-27 Sealantium Medical Ltd. Fibrinogen-based tissue adhesive patches
RU2678592C1 (en) 2013-12-11 2019-01-30 Ферросан Медикал Дивайсиз А/С Dry composition comprising extrusion enhancer
JP6726852B2 (en) * 2014-10-13 2020-07-22 フェッローサン メディカル ディバイス エー/エス Dry composition for use in hemostasis and wound healing
JP6747650B2 (en) 2014-12-24 2020-08-26 フェロサン メディカル デバイシーズ エイ/エス Syringe for holding and mixing the first substance and the second substance
EP3270950B1 (en) * 2015-03-20 2021-04-21 Université de Paris Isolated peptides and fragments thereof from fibrinogen for use as drugs, particularly in skin inflammatory diseases
EP3305259A4 (en) * 2015-05-29 2019-02-13 Kyowa Limited Medical tape
AU2016290433B2 (en) 2015-07-03 2018-05-24 Ferrosan Medical Devices A/S Syringe for mixing two components and for retaining a vacuum in a storage condition
US11471556B2 (en) 2015-10-19 2022-10-18 Sealantium Medical Ltd. Fibrinogen-based tissue adhesive patch
CN107485728A (en) * 2016-06-12 2017-12-19 胡庆柳 A kind of collagen fibrous proteins compound hemostatic plaster and preparation method thereof
RU2628809C1 (en) * 2016-06-30 2017-08-22 Федеральное государственное бюджетное учреждение Гематологический научный центр Министерства здравоохранения Российской Федерации (ФГБУ ГНЦ Минздрава России) Hemostatic sponge and method of its production
CN106860907B (en) * 2016-12-30 2019-10-29 深圳市新指南医学科技发展有限公司 A kind of hemostatic gauze
BR102017008024B1 (en) * 2017-04-18 2022-10-04 Cristália Produtos Químicos Farmacêuticos Ltda DEVICE FOR APPLICATION OF FIBRIN BIOPOLYMERS
CN109381731B (en) * 2017-08-02 2021-04-13 长沙海润生物技术有限公司 Medical biological dressing and preparation method thereof
KR101989054B1 (en) * 2017-11-28 2019-06-13 (주)다림티센 Hemostatic agent and container containing the same
IL256405A (en) 2017-12-19 2018-01-31 Omrix Biopharmaceuticals Ltd Wound dressing and a method for producing the same
US11662299B2 (en) 2018-03-22 2023-05-30 Sealantium Medical Ltd Method for determining the adhesive force of a hemostatic tissue sealant patch
EP3790600B1 (en) 2018-05-09 2023-12-27 Ferrosan Medical Devices A/S Method for preparing a haemostatic composition
CN108904873A (en) * 2018-06-25 2018-11-30 东莞市联洲知识产权运营管理有限公司 A kind of preparation method for the luffa medical gel dressing that netted loofah fiber element/silk fibroin powder is modified
CN109009667A (en) * 2018-08-22 2018-12-18 广东食品药品职业学院 A kind of spiral adhesive bandage and preparation method thereof
CN111035799A (en) * 2019-01-02 2020-04-21 浙江西安交通大学研究院 Self-propelled particle for obtaining self-propelled foaming tissue sealant and preparation method thereof
RU2712763C1 (en) * 2019-02-22 2020-01-31 Вероника Андреевна Гусева Method for complex treatment of ligament injures and tendons in horses
CN113727740A (en) 2019-02-26 2021-11-30 重庆医科大学附属口腔医院 Medical adhesive and preparation method and application thereof
RU2700497C1 (en) * 2019-04-26 2019-09-18 Государственное автономное учреждение здравоохранения "Республиканская клиническая больница Министерства здравоохранения Республики Татарстан" Method for treating complicated biophosphonate osteomyelitis of jaw bones
CN111420114A (en) * 2020-04-01 2020-07-17 浙江西安交通大学研究院 Self-pushing type hemostatic gauze/dressing
CN112569400A (en) * 2020-11-13 2021-03-30 东华大学 Janus hemostatic dressing and preparation method thereof
CN115814142A (en) * 2022-11-25 2023-03-21 大连大学 Wound repair composite membrane with ion response performance, preparation method and application

Citations (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1975504A (en) * 1929-12-07 1934-10-02 Richard Schreiber Gastell Process and apparatus for preparing artificial threads
US2533004A (en) * 1943-10-27 1950-12-05 John D Ferry Fibrin clots and methods for preparing the same
US3012893A (en) * 1959-01-06 1961-12-12 Gen Foods Corp Gasified confection and method of making the same
US3089875A (en) * 1961-02-23 1963-05-14 Olin Mathieson Alkyl, aryl substituted melems
US3523807A (en) * 1966-11-25 1970-08-11 Mihaly Gerendas Method of making a cross-linked fibrin prosthesis
US3723244A (en) * 1971-01-18 1973-03-27 Atomic Energy Commission Fibrous fibrin sheet and method for producing same
US4265233A (en) * 1978-04-12 1981-05-05 Unitika Ltd. Material for wound healing
US4298598A (en) * 1979-02-15 1981-11-03 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Tissue adhesive
US4321711A (en) * 1978-10-18 1982-03-30 Sumitomo Electric Industries, Ltd. Vascular prosthesis
US4359049A (en) * 1980-04-02 1982-11-16 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Apparatus for applying a tissue adhesive on the basis of human or animal proteins
US4362567A (en) * 1979-02-15 1982-12-07 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Tissue adhesive
US4373519A (en) * 1981-06-26 1983-02-15 Minnesota Mining And Manufacturing Company Composite wound dressing
US4377159A (en) * 1981-06-29 1983-03-22 Minnesota Mining And Manufacturing Company Pressure bandages and methods for making the same
US4393041A (en) * 1980-04-25 1983-07-12 International Minerals & Chemical Corp. Fibrin binder/carrier for active biochemical agents
US4394370A (en) * 1981-09-21 1983-07-19 Jefferies Steven R Bone graft material for osseous defects and method of making same
US4407787A (en) * 1980-10-03 1983-10-04 Dr. Ruhland Nachf. Gmbh Collagenous dressing
US4427650A (en) * 1981-06-25 1984-01-24 Serapharm Michael Stroetmann Enriched plasma derivative for advancement of wound closure and healing
US4427651A (en) * 1981-06-25 1984-01-24 Serapharm Michael Stroetmann Enriched plasma derivative for enhancement of wound closure and coverage
US4442655A (en) * 1981-06-25 1984-04-17 Serapharm Michael Stroetmann Fibrinogen-containing dry preparation, manufacture and use thereof
US4453939A (en) * 1981-02-16 1984-06-12 Hormon-Chemie Munchen Gmbh Composition for sealing and healing wounds
US4472840A (en) * 1981-09-21 1984-09-25 Jefferies Steven R Method of inducing osseous formation by implanting bone graft material
US4516276A (en) * 1979-12-18 1985-05-14 Oscobal Ag Bone substitute and a method of production thereof
US4548763A (en) * 1983-12-05 1985-10-22 Allied Corporation Preparation of vinylphosphonate diesters
US4597960A (en) * 1983-04-19 1986-07-01 Cohen Edgar C Microencapsulated astringent hemostatic agents and methods of use
US4600574A (en) * 1984-03-21 1986-07-15 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Method of producing a tissue adhesive
US4606337A (en) * 1982-04-19 1986-08-19 Serapharm Gmbh & Co. Kg Resorptive sheet material for closing and healing wounds and method of making the same
US4617293A (en) * 1981-05-13 1986-10-14 Merck Patent Gesellschaft Mit Beschraenkter Haftung Flavonoid phosphate salts of aminoglycoside antibiotics
US4619913A (en) * 1984-05-29 1986-10-28 Matrix Pharmaceuticals, Inc. Treatments employing drug-containing matrices for introduction into cellular lesion areas
US4619989A (en) * 1981-05-05 1986-10-28 The Regents Of The University Of Cal. Bone morphogenetic protein composition
US4627879A (en) * 1984-09-07 1986-12-09 The Trustees Of Columbia University In The City Of New York Fibrin adhesive prepared as a concentrate from single donor fresh frozen plasma
US4631055A (en) * 1984-03-29 1986-12-23 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Apparatus for applying a tissue adhesive
US4642120A (en) * 1983-03-23 1987-02-10 Ramot University Authority For Applied Research And Industrial Development Ltd. Repair of cartilage and bones
US4714457A (en) * 1986-09-15 1987-12-22 Robert Alterbaum Method and apparatus for use in preparation of fibrinogen from a patient's blood
US4717717A (en) * 1986-11-05 1988-01-05 Ethicon, Inc. Stabilized compositions containing epidermal growth factor
US4761471A (en) * 1980-08-04 1988-08-02 The Regents Of The University Of California Bone morphogenetic protein composition
US4789732A (en) * 1980-08-04 1988-12-06 Regents Of The University Of California Bone morphogenetic protein composition
US4816339A (en) * 1987-04-28 1989-03-28 Baxter International Inc. Multi-layered poly(tetrafluoroethylene)/elastomer materials useful for in vivo implantation
US4820626A (en) * 1985-06-06 1989-04-11 Thomas Jefferson University Method of treating a synthetic or naturally occuring surface with microvascular endothelial cells, and the treated surface itself
US4837379A (en) * 1988-06-02 1989-06-06 Organogenesis Inc. Fibrin-collagen tissue equivalents and methods for preparation thereof
US4861757A (en) * 1986-11-14 1989-08-29 Institute Of Molecular Biology Wound healing and bone regeneration using PDGF and IGF-I
US4874746A (en) * 1987-12-22 1989-10-17 Institute Of Molecular Biology, Inc. Wound headling composition of TGF-alpha and PDGF
US4909251A (en) * 1988-05-31 1990-03-20 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Tissue adhesive
US4928603A (en) * 1984-09-07 1990-05-29 The Trustees Of Columbia University In The City Of New York Method of preparing a cryoprecipitated suspension and use thereof
US4952403A (en) * 1987-06-19 1990-08-28 President And Fellows Of Harvard College Implants for the promotion of healing of meniscal tissue
US4969880A (en) * 1989-04-03 1990-11-13 Zamierowski David S Wound dressing and treatment method
US4983581A (en) * 1988-05-20 1991-01-08 Institute Of Molecular Biology, Inc. Wound healing composition of IGF-I and TGF-β
US4997425A (en) * 1986-10-31 1991-03-05 Nippon Zeon Co., Ltd. Wound dressing
US5019559A (en) * 1986-11-14 1991-05-28 President And Fellows Of Harvard College Wound healing using PDGF and IGF-II
US5023082A (en) * 1986-05-18 1991-06-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sustained-release pharmaceutical compositions
US5024742A (en) * 1988-02-24 1991-06-18 Cedars-Sinai Medical Center Method of crosslinking amino acid containing polymers using photoactivatable chemical crosslinkers
US5030215A (en) * 1990-01-03 1991-07-09 Cryolife, Inc. Preparation of fibrinogen/factor XIII precipitate
US5034375A (en) * 1988-08-10 1991-07-23 Institute Of Molecular Biology, Inc. Process of wound healing using PDGF and EGF
US5035887A (en) * 1989-09-07 1991-07-30 Institute Of Moelcular Biology, Inc. Wound healing composition of IL-1 and PDGF or IGF-1
US5059123A (en) * 1990-05-14 1991-10-22 Jernberg Gary R Periodontal barrier and method for aiding periodontal tissue regeneration
US5100396A (en) * 1989-04-03 1992-03-31 Zamierowski David S Fluidic connection system and method
US5124155A (en) * 1988-06-21 1992-06-23 Chiron Ophthalmics, Inc. Fibronectin wound-healing dressings
US5139527A (en) * 1987-12-17 1992-08-18 Immuno Aktiengesellschaft Biologic absorbable implant material for filling and closing soft tissue cavities and method of its preparation
US5171579A (en) * 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
US5171318A (en) * 1987-11-09 1992-12-15 Chiron Ophthalmics, Inc. Treated corneal prosthetic device
US5206023A (en) * 1991-01-31 1993-04-27 Robert F. Shaw Method and compositions for the treatment and repair of defects or lesions in cartilage
US5219328A (en) * 1990-01-03 1993-06-15 Cryolife, Inc. Fibrin sealant delivery method
US5226877A (en) * 1989-06-23 1993-07-13 Epstein Gordon H Method and apparatus for preparing fibrinogen adhesive from whole blood
US5290552A (en) * 1988-05-02 1994-03-01 Matrix Pharmaceutical, Inc./Project Hear Surgical adhesive material
US5702715A (en) * 1995-10-27 1997-12-30 Drying Technology Reinforced biological sealants
US5716645A (en) * 1991-09-05 1998-02-10 Baxter International Inc. Topical fibrinogen complex
US5723010A (en) * 1995-03-31 1998-03-03 Toyo Boseki Kabushiki Kaisha Medical device and method for producing the same
US5763411A (en) * 1992-10-08 1998-06-09 Bristol-Myers Squibb Company Nondynamic fibrin monomer on bandages, sutures, prostheses and dressings
US6054122A (en) * 1990-11-27 2000-04-25 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US6056970A (en) * 1998-05-07 2000-05-02 Genzyme Corporation Compositions comprising hemostatic compounds and bioabsorbable polymers
US6117425A (en) * 1990-11-27 2000-09-12 The American National Red Cross Supplemented and unsupplemented tissue sealants, method of their production and use
US6124273A (en) * 1995-06-09 2000-09-26 Chitogenics, Inc. Chitin hydrogels, methods of their production and use
US6197325B1 (en) * 1990-11-27 2001-03-06 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US6447774B1 (en) * 1998-11-18 2002-09-10 Aventis Behring Gmbh Stabilized protein preparations for a tissue adhesive
US6762336B1 (en) * 1998-01-19 2004-07-13 The American National Red Cross Hemostatic sandwich bandage
US20060155234A1 (en) * 2002-09-10 2006-07-13 American National Red Cross Hemostatic dressing
US7189410B1 (en) * 1990-11-27 2007-03-13 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2492458A (en) * 1944-12-08 1949-12-27 Jr Edgar A Bering Fibrin foam
US3089815A (en) * 1951-10-11 1963-05-14 Lieb Hans Injectable pharmaceutical preparation, and a method of making same
GB1584080A (en) 1977-12-05 1981-02-04 Ethicon Inc Absorbable hemostatic composition
DE3037270A1 (en) 1980-10-02 1982-05-19 Ulatowski, Lothar, Dr.med., 5630 Remscheid Fibrin-antibiotic composite chain - for use as an antiseptic implant
JPS61178927A (en) * 1981-06-25 1986-08-11 セラフアルム ジ−エムビ−エイチ アンド カンパニ− ケイジイ Dry medicine containing fibrinogen and manufacture
AT369990B (en) 1981-07-28 1983-02-25 Immuno Ag METHOD FOR PRODUCING A TISSUE ADHESIVE
US4706662A (en) 1981-12-11 1987-11-17 Johnson & Johnson Products, Inc. Film dressing with fabric backing
FR2589737A1 (en) 1985-11-12 1987-05-15 Dow Corning Sa METHODS OF MANUFACTURING DRESSINGS
DE3622642A1 (en) 1986-07-05 1988-01-14 Behringwerke Ag ONE-COMPONENT TISSUE ADHESIVE AND METHOD FOR THE PRODUCTION THEREOF
NZ226171A (en) 1987-09-18 1990-06-26 Ethicon Inc Gel formulation containing polypeptide growth factor
EP0443724B1 (en) 1990-02-20 1999-03-17 Baxter International Inc. Viral-safe purified human thrombin
JPH05192387A (en) 1990-11-08 1993-08-03 Matrix Pharmaceut Inc Fibrin for biomedical purpose/ collagenic coat
GB9206509D0 (en) 1992-03-25 1992-05-06 Jevco Ltd Heteromorphic sponges containing active agents
WO1996022115A1 (en) * 1995-01-16 1996-07-25 Baxter International Inc. Self-supporting sheet-like material of cross-linked fibrin for preventing post operative adhesions
WO1997028832A1 (en) * 1996-02-06 1997-08-14 New Generation Medical Corporation Composition for sealing wounds
JP2000510357A (en) 1996-04-04 2000-08-15 イムノ・アクチエンゲゼルシャフト Hemostatic sponge based on collagen
ATE254934T1 (en) * 1998-05-19 2003-12-15 American Nat Red Cross MULTI-LAYER HEMOSTATIC BANDAGE CONTAINING A LAYER OF THROMBIN BETWEEN TWO LAYERS OF FIBRINOGEN
NZ527165A (en) * 2001-01-25 2005-02-25 Nycomed Pharma As A collagen or flexible, elastic carrier with solid fibrinogen and solid thrombin for haemostasis, tissue sealing and tissue gluing
WO2004010913A1 (en) 2001-07-25 2004-02-05 Us Army Medical Research & Materiel Command Fibrinogen bandages and methods
ES2365709T3 (en) * 2003-01-09 2011-10-10 Polyganics B.V. BIOMEDICAL FOAMS.
RU2235539C1 (en) 2003-04-25 2004-09-10 Филатов Владимир Николаевич Method for preparing powder-like material for bleeding cease
US8119160B2 (en) * 2004-06-29 2012-02-21 Ethicon, Inc. Hemostatic compositions and devices
DK2052746T3 (en) * 2004-10-20 2014-12-08 Ethicon Inc Absorbable hemostatic patch
WO2008019126A2 (en) 2006-08-04 2008-02-14 Stb Lifesaving Technologies, Inc. Process for production of solid wound dressing

Patent Citations (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1975504A (en) * 1929-12-07 1934-10-02 Richard Schreiber Gastell Process and apparatus for preparing artificial threads
US2533004A (en) * 1943-10-27 1950-12-05 John D Ferry Fibrin clots and methods for preparing the same
US3012893A (en) * 1959-01-06 1961-12-12 Gen Foods Corp Gasified confection and method of making the same
US3089875A (en) * 1961-02-23 1963-05-14 Olin Mathieson Alkyl, aryl substituted melems
US3523807A (en) * 1966-11-25 1970-08-11 Mihaly Gerendas Method of making a cross-linked fibrin prosthesis
US3723244A (en) * 1971-01-18 1973-03-27 Atomic Energy Commission Fibrous fibrin sheet and method for producing same
US4265233A (en) * 1978-04-12 1981-05-05 Unitika Ltd. Material for wound healing
US4321711A (en) * 1978-10-18 1982-03-30 Sumitomo Electric Industries, Ltd. Vascular prosthesis
US4377572A (en) * 1979-02-15 1983-03-22 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Tissue adhesive
US4362567A (en) * 1979-02-15 1982-12-07 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Tissue adhesive
US4298598A (en) * 1979-02-15 1981-11-03 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Tissue adhesive
US4414976A (en) * 1979-02-15 1983-11-15 Immuno Aktiengesellschaft Fur Chemischmedizinische Produkte Tissue adhesive
US4516276A (en) * 1979-12-18 1985-05-14 Oscobal Ag Bone substitute and a method of production thereof
US4359049A (en) * 1980-04-02 1982-11-16 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Apparatus for applying a tissue adhesive on the basis of human or animal proteins
US4393041A (en) * 1980-04-25 1983-07-12 International Minerals & Chemical Corp. Fibrin binder/carrier for active biochemical agents
US4761471A (en) * 1980-08-04 1988-08-02 The Regents Of The University Of California Bone morphogenetic protein composition
US4789732A (en) * 1980-08-04 1988-12-06 Regents Of The University Of California Bone morphogenetic protein composition
US4407787A (en) * 1980-10-03 1983-10-04 Dr. Ruhland Nachf. Gmbh Collagenous dressing
US4453939A (en) * 1981-02-16 1984-06-12 Hormon-Chemie Munchen Gmbh Composition for sealing and healing wounds
US4619989A (en) * 1981-05-05 1986-10-28 The Regents Of The University Of Cal. Bone morphogenetic protein composition
US4617293A (en) * 1981-05-13 1986-10-14 Merck Patent Gesellschaft Mit Beschraenkter Haftung Flavonoid phosphate salts of aminoglycoside antibiotics
US4427651A (en) * 1981-06-25 1984-01-24 Serapharm Michael Stroetmann Enriched plasma derivative for enhancement of wound closure and coverage
US4442655A (en) * 1981-06-25 1984-04-17 Serapharm Michael Stroetmann Fibrinogen-containing dry preparation, manufacture and use thereof
US4427650A (en) * 1981-06-25 1984-01-24 Serapharm Michael Stroetmann Enriched plasma derivative for advancement of wound closure and healing
US4373519A (en) * 1981-06-26 1983-02-15 Minnesota Mining And Manufacturing Company Composite wound dressing
US4377159A (en) * 1981-06-29 1983-03-22 Minnesota Mining And Manufacturing Company Pressure bandages and methods for making the same
US4472840A (en) * 1981-09-21 1984-09-25 Jefferies Steven R Method of inducing osseous formation by implanting bone graft material
US4394370A (en) * 1981-09-21 1983-07-19 Jefferies Steven R Bone graft material for osseous defects and method of making same
US4606337A (en) * 1982-04-19 1986-08-19 Serapharm Gmbh & Co. Kg Resorptive sheet material for closing and healing wounds and method of making the same
US4683142A (en) * 1982-04-19 1987-07-28 Eberhard Zimmermann Resorptive sheet material for closing and healing wounds and method of making the same
US4642120A (en) * 1983-03-23 1987-02-10 Ramot University Authority For Applied Research And Industrial Development Ltd. Repair of cartilage and bones
US4597960A (en) * 1983-04-19 1986-07-01 Cohen Edgar C Microencapsulated astringent hemostatic agents and methods of use
US4548763A (en) * 1983-12-05 1985-10-22 Allied Corporation Preparation of vinylphosphonate diesters
US4600574A (en) * 1984-03-21 1986-07-15 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Method of producing a tissue adhesive
US4631055A (en) * 1984-03-29 1986-12-23 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Apparatus for applying a tissue adhesive
US4619913A (en) * 1984-05-29 1986-10-28 Matrix Pharmaceuticals, Inc. Treatments employing drug-containing matrices for introduction into cellular lesion areas
USRE33375E (en) * 1984-05-29 1990-10-09 Matrix Pharmaceuticals, Inc. Treatments employing drug-containing matrices for introduction into cellular lesion areas
US4627879A (en) * 1984-09-07 1986-12-09 The Trustees Of Columbia University In The City Of New York Fibrin adhesive prepared as a concentrate from single donor fresh frozen plasma
US4928603A (en) * 1984-09-07 1990-05-29 The Trustees Of Columbia University In The City Of New York Method of preparing a cryoprecipitated suspension and use thereof
US4820626A (en) * 1985-06-06 1989-04-11 Thomas Jefferson University Method of treating a synthetic or naturally occuring surface with microvascular endothelial cells, and the treated surface itself
US5023082A (en) * 1986-05-18 1991-06-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sustained-release pharmaceutical compositions
US4714457A (en) * 1986-09-15 1987-12-22 Robert Alterbaum Method and apparatus for use in preparation of fibrinogen from a patient's blood
US4997425A (en) * 1986-10-31 1991-03-05 Nippon Zeon Co., Ltd. Wound dressing
US4717717A (en) * 1986-11-05 1988-01-05 Ethicon, Inc. Stabilized compositions containing epidermal growth factor
US4861757A (en) * 1986-11-14 1989-08-29 Institute Of Molecular Biology Wound healing and bone regeneration using PDGF and IGF-I
US5019559A (en) * 1986-11-14 1991-05-28 President And Fellows Of Harvard College Wound healing using PDGF and IGF-II
US4816339A (en) * 1987-04-28 1989-03-28 Baxter International Inc. Multi-layered poly(tetrafluoroethylene)/elastomer materials useful for in vivo implantation
US4952403A (en) * 1987-06-19 1990-08-28 President And Fellows Of Harvard College Implants for the promotion of healing of meniscal tissue
US5171318A (en) * 1987-11-09 1992-12-15 Chiron Ophthalmics, Inc. Treated corneal prosthetic device
US5139527A (en) * 1987-12-17 1992-08-18 Immuno Aktiengesellschaft Biologic absorbable implant material for filling and closing soft tissue cavities and method of its preparation
US4874746A (en) * 1987-12-22 1989-10-17 Institute Of Molecular Biology, Inc. Wound headling composition of TGF-alpha and PDGF
US5024742A (en) * 1988-02-24 1991-06-18 Cedars-Sinai Medical Center Method of crosslinking amino acid containing polymers using photoactivatable chemical crosslinkers
US5431790A (en) * 1988-02-24 1995-07-11 Cedars-Sinai Medical Center Method of crosslinking amino acid containing polymers using photoactivatable chemical crosslinkers
US5294314A (en) * 1988-02-24 1994-03-15 Cedars-Sinai Medical Center Method of crosslinking amino acid containing polymers using photoactivatable chemical crosslinkers
US5290552A (en) * 1988-05-02 1994-03-01 Matrix Pharmaceutical, Inc./Project Hear Surgical adhesive material
US4983581A (en) * 1988-05-20 1991-01-08 Institute Of Molecular Biology, Inc. Wound healing composition of IGF-I and TGF-β
US4909251A (en) * 1988-05-31 1990-03-20 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Tissue adhesive
US4837379A (en) * 1988-06-02 1989-06-06 Organogenesis Inc. Fibrin-collagen tissue equivalents and methods for preparation thereof
US5124155A (en) * 1988-06-21 1992-06-23 Chiron Ophthalmics, Inc. Fibronectin wound-healing dressings
US5034375A (en) * 1988-08-10 1991-07-23 Institute Of Molecular Biology, Inc. Process of wound healing using PDGF and EGF
US5100396A (en) * 1989-04-03 1992-03-31 Zamierowski David S Fluidic connection system and method
US4969880A (en) * 1989-04-03 1990-11-13 Zamierowski David S Wound dressing and treatment method
US5226877A (en) * 1989-06-23 1993-07-13 Epstein Gordon H Method and apparatus for preparing fibrinogen adhesive from whole blood
US5035887A (en) * 1989-09-07 1991-07-30 Institute Of Moelcular Biology, Inc. Wound healing composition of IL-1 and PDGF or IGF-1
US5219328A (en) * 1990-01-03 1993-06-15 Cryolife, Inc. Fibrin sealant delivery method
US5030215A (en) * 1990-01-03 1991-07-09 Cryolife, Inc. Preparation of fibrinogen/factor XIII precipitate
US5059123A (en) * 1990-05-14 1991-10-22 Jernberg Gary R Periodontal barrier and method for aiding periodontal tissue regeneration
US6054122A (en) * 1990-11-27 2000-04-25 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US7189410B1 (en) * 1990-11-27 2007-03-13 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US6197325B1 (en) * 1990-11-27 2001-03-06 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US6117425A (en) * 1990-11-27 2000-09-12 The American National Red Cross Supplemented and unsupplemented tissue sealants, method of their production and use
US5368858A (en) * 1991-01-31 1994-11-29 Robert F. Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage
US5206023A (en) * 1991-01-31 1993-04-27 Robert F. Shaw Method and compositions for the treatment and repair of defects or lesions in cartilage
US5716645A (en) * 1991-09-05 1998-02-10 Baxter International Inc. Topical fibrinogen complex
US5171579A (en) * 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
US5763411A (en) * 1992-10-08 1998-06-09 Bristol-Myers Squibb Company Nondynamic fibrin monomer on bandages, sutures, prostheses and dressings
US5723010A (en) * 1995-03-31 1998-03-03 Toyo Boseki Kabushiki Kaisha Medical device and method for producing the same
US6124273A (en) * 1995-06-09 2000-09-26 Chitogenics, Inc. Chitin hydrogels, methods of their production and use
US5702715A (en) * 1995-10-27 1997-12-30 Drying Technology Reinforced biological sealants
US6762336B1 (en) * 1998-01-19 2004-07-13 The American National Red Cross Hemostatic sandwich bandage
US6056970A (en) * 1998-05-07 2000-05-02 Genzyme Corporation Compositions comprising hemostatic compounds and bioabsorbable polymers
US6447774B1 (en) * 1998-11-18 2002-09-10 Aventis Behring Gmbh Stabilized protein preparations for a tissue adhesive
US20060155234A1 (en) * 2002-09-10 2006-07-13 American National Red Cross Hemostatic dressing

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8834914B2 (en) 2003-12-11 2014-09-16 Zimmer, Inc. Treatment methods using a particulate cadaveric allogenic juvenile cartilage particles
US8784863B2 (en) 2003-12-11 2014-07-22 Zimmer, Inc. Particulate cadaveric allogenic cartilage system
US8765165B2 (en) 2003-12-11 2014-07-01 Zimmer, Inc. Particulate cartilage system
US8652507B2 (en) 2003-12-11 2014-02-18 Zimmer, Inc. Juvenile cartilage composition
US8524268B2 (en) 2003-12-11 2013-09-03 Zimmer, Inc. Cadaveric allogenic human juvenile cartilage implant
US8518433B2 (en) 2003-12-11 2013-08-27 Zimmer, Inc. Method of treating an osteochondral defect
US8480757B2 (en) 2005-08-26 2013-07-09 Zimmer, Inc. Implants and methods for repair, replacement and treatment of disease
US8235939B2 (en) 2006-02-06 2012-08-07 Kci Licensing, Inc. System and method for purging a reduced pressure apparatus during the administration of reduced pressure treatment
US20070219497A1 (en) * 2006-02-06 2007-09-20 Johnson Royce W System and method for purging a reduced pressure apparatus during the administration of reduced pressure treatment
US8029498B2 (en) 2006-03-14 2011-10-04 Kci Licensing Inc. System for percutaneously administering reduced pressure treatment using balloon dissection
US20090157017A1 (en) * 2006-03-14 2009-06-18 Archel Ambrosio Bioresorbable foaming tissue dressing
US9456860B2 (en) 2006-03-14 2016-10-04 Kci Licensing, Inc. Bioresorbable foaming tissue dressing
US9050402B2 (en) 2006-03-14 2015-06-09 Kci Licensing, Inc. Method for percutaneously administering reduced pressure treatment using balloon dissection
US8939933B2 (en) 2006-03-14 2015-01-27 Kci Licensing, Inc. Manifolds, systems, and methods for administering reduced pressure to a subcutaneous tissue site
US8267918B2 (en) 2006-03-14 2012-09-18 Kci Licensing, Inc. System and method for percutaneously administering reduced pressure treatment using a flowable manifold
US20070219585A1 (en) * 2006-03-14 2007-09-20 Cornet Douglas A System for administering reduced pressure treatment having a manifold with a primary flow passage and a blockage prevention member
US20080033324A1 (en) * 2006-03-14 2008-02-07 Cornet Douglas A System for administering reduced pressure treatment having a manifold with a primary flow passage and a blockage prevention member
US8617140B2 (en) 2006-03-14 2013-12-31 Kci Licensing, Inc. System for percutaneously administering reduced pressure treatment using balloon dissection
US20070219489A1 (en) * 2006-03-14 2007-09-20 Johnson Royce W Method for percutaneously administering reduced pressure treatment using balloon dissection
US20100168688A1 (en) * 2006-03-14 2010-07-01 Carl Joseph Santora Manifolds, systems, and methods for administering reduced pressure to a subcutaneous tissue site
US8497121B2 (en) 2006-12-20 2013-07-30 Zimmer Orthobiologics, Inc. Method of obtaining viable small tissue particles and use for tissue repair
US20080154233A1 (en) * 2006-12-20 2008-06-26 Zimmer Orthobiologics, Inc. Apparatus for delivering a biocompatible material to a surgical site and method of using same
US20090012629A1 (en) * 2007-04-12 2009-01-08 Isto Technologies, Inc. Compositions and methods for tissue repair
US9138318B2 (en) 2007-04-12 2015-09-22 Zimmer, Inc. Apparatus for forming an implant
US20100172889A1 (en) * 2008-12-05 2010-07-08 Catchmark Jeffrey M Degradable biomolecule compositions
WO2010078209A3 (en) * 2008-12-31 2010-11-04 Kci Licensing, Inc. Bioresorbable foaming tissue dressing
US9089584B2 (en) 2009-05-28 2015-07-28 Profibrix B.V. Treatment of tissue adhesion
US20120070477A1 (en) * 2009-05-28 2012-03-22 Profibrix B.V. Dry powder fibrin sealant
US9119897B2 (en) * 2009-05-28 2015-09-01 Profibrix B.V. Dry powder fibrin sealant
US20120177718A1 (en) * 2009-06-11 2012-07-12 The Chemo-Sero-Therapeutic Research Institute Wound-covering material
US8273369B2 (en) 2010-05-17 2012-09-25 Ethicon, Inc. Reinforced absorbable synthetic matrix for hemostatic applications
US8383147B2 (en) 2010-05-17 2013-02-26 Ethicon, Inc. Reinforced absorbable synthetic matrix for hemostatic applications
US20140081192A1 (en) * 2011-03-21 2014-03-20 KET Kunststoff-und Elaststoff-und Elasttechnik GmbH Liegau-Augustustutusbad Primary dressing for moist wound healing, and method for producing said primary dressing
US10010452B2 (en) * 2011-03-21 2018-07-03 Ket Kunststoff-Und Elasttechnik Gmbh Liegau-Augustusbad Primary dressing for moist wound healing, and method for producing said primary dressing
US9561300B2 (en) 2011-09-26 2017-02-07 Yes, Inc. Hemostatic compositions and dressings for bleeding
US10159762B2 (en) 2011-09-26 2018-12-25 Yes, Inc. Hemostatic compositions and dressings for bleeding
US10167447B2 (en) 2012-12-21 2019-01-01 Zimmer, Inc. Supports and methods for promoting integration of cartilage tissue explants
US10202517B2 (en) 2013-07-26 2019-02-12 The Penn State Research Foundation Polymer compositions and coatings
US11781032B2 (en) 2013-07-26 2023-10-10 The Penn State Research Foundation Polymer compositions and coatings
CN104189941A (en) * 2014-09-03 2014-12-10 北京化工大学 Chitosan gel haemostatic material and preparation method thereof
US10137222B2 (en) 2015-03-27 2018-11-27 3M Innovative Properties Company Fibrin composition, method and wound articles
US10940233B2 (en) 2016-10-05 2021-03-09 3M Innovative Properties Company Fibrinogen composition, method and wound articles
US11827754B2 (en) 2016-10-05 2023-11-28 3M Innovative Properties Company Fibrin composition comprising carrier material, method and wound articles

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